| 1 | Mov. Disord. 2000 Mar 15: 201-11 |
|---|---|
| PMID | 10752567 |
| Title | Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson's disease. |
| Abstract | Our experience with atypical antipsychotics in patients with PD is that their motor effects are not predictable. The multiple reports concerning clozapine's beneficial effects on tremor, dystonia, nocturnal akathisia, and dyskinesias all underscore this observation. However, the appearance of even minor degrees of parkinsonism in normal volunteers or schizophrenics should suggest that an antipsychotic will not be well-tolerated in patients with PD. The treatment of PD is probably the most stringent test of a drug's freedom from parkinsonian side effects. The data from trials in schizophrenia concerning parkinsonian effects cannot always be confidently interpreted. Virtually all subjects in these trials have been treated with typical neuroleptics until shortly before study entry. Because the parkinsonian side effects of these drugs may persist for several months, patients may still show declining levels of parkinsonism even when placed on a drug that induces it if this effect is milder than that induced by the pre-study neuroleptic. Depending on the pre-study drug used and the duration of the study, distinguishing placebo from a low-potency neuroleptic may be impossible. Furthermore, the standard measure of parkinsonism in psychiatric studies is the Simpson-Angus scale which is heavily weighted toward rigidity and may underscore bradykinesia, gait, and posture abnormalities. The prolactin response to an antipsychotic drug may turn out to be a good predictor of its freedom from parkinsonian side effects. That would fit with the data presented above of clozapine and quetiapine having less parkinsonian effects, olanzapine having more but variable effects and risperidone being poorly tolerated. With the data presented above, comprising a current review of all reports of the use of atypical antipsychotics in PD that we could locate, we can say little with certainty. The only drug with confirmed benefit without worsening parkinsonism is clozapine. Open-label trials involving over 400 patients and two multicenter, placebo-controlled, double-blind trials have demonstrated that it is effective in treating the psychosis. It improves tremor, does not worsen other motor functions to any significant extent, and is safe at low doses. Limited data provide conflicting information on both risperidone and olanzapine. Quetiapine seems to be well-tolerated with some, but definitely less, worsening of PD motor features than risperidone and olanzapine. Based on the current literature, our personal experience, and anecdotal experience of other PD specialists which we solicited, we will venture our own interpretation and recommendations. We think risperidone is poorly tolerated and should be used only as a last resort; that olanzapine is better than risperidone but will, in a majority of patients with PD, worsen motor function. We are optimistic, but not yet convinced, that quetiapine may prove to be as effective and better tolerated than clozapine. It will not require cumbersome monitoring because it does not induce a blood dyscrasia. We therefore recommend that DP be treated in the following manner. First, the anti-PD medications should be simplified and reduced as much as tolerated. We think, in general, side effects multiply more with increasing numbers of drugs than with drug dose, so that patients are more likely to tolerate a higher dose of levodopa than a lower dose of levodopa combined with other adjunctive anti-PD medications. In reducing anti-PD medications, we recommend tapering and stopping, if necessary, the drugs with the highest risk-to-benefit ratio first. Anticholinergics are stopped first, then selegiline, dopamine agonists, amantadine, and finally COMT inhibitors, which have no psychotomimetic action of their own. Finally, levodopa is reduced. Generally, a point is reached at which the anti-PD medications cannot be reduced without jeopardizing motor function. If psychosis persists at this point, then an antipsychotic is added. (ABS |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 2 | Mov. Disord. 2000 Mar 15: 201-11 |
| PMID | 10752567 |
| Title | Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson's disease. |
| Abstract | Our experience with atypical antipsychotics in patients with PD is that their motor effects are not predictable. The multiple reports concerning clozapine's beneficial effects on tremor, dystonia, nocturnal akathisia, and dyskinesias all underscore this observation. However, the appearance of even minor degrees of parkinsonism in normal volunteers or schizophrenics should suggest that an antipsychotic will not be well-tolerated in patients with PD. The treatment of PD is probably the most stringent test of a drug's freedom from parkinsonian side effects. The data from trials in schizophrenia concerning parkinsonian effects cannot always be confidently interpreted. Virtually all subjects in these trials have been treated with typical neuroleptics until shortly before study entry. Because the parkinsonian side effects of these drugs may persist for several months, patients may still show declining levels of parkinsonism even when placed on a drug that induces it if this effect is milder than that induced by the pre-study neuroleptic. Depending on the pre-study drug used and the duration of the study, distinguishing placebo from a low-potency neuroleptic may be impossible. Furthermore, the standard measure of parkinsonism in psychiatric studies is the Simpson-Angus scale which is heavily weighted toward rigidity and may underscore bradykinesia, gait, and posture abnormalities. The prolactin response to an antipsychotic drug may turn out to be a good predictor of its freedom from parkinsonian side effects. That would fit with the data presented above of clozapine and quetiapine having less parkinsonian effects, olanzapine having more but variable effects and risperidone being poorly tolerated. With the data presented above, comprising a current review of all reports of the use of atypical antipsychotics in PD that we could locate, we can say little with certainty. The only drug with confirmed benefit without worsening parkinsonism is clozapine. Open-label trials involving over 400 patients and two multicenter, placebo-controlled, double-blind trials have demonstrated that it is effective in treating the psychosis. It improves tremor, does not worsen other motor functions to any significant extent, and is safe at low doses. Limited data provide conflicting information on both risperidone and olanzapine. Quetiapine seems to be well-tolerated with some, but definitely less, worsening of PD motor features than risperidone and olanzapine. Based on the current literature, our personal experience, and anecdotal experience of other PD specialists which we solicited, we will venture our own interpretation and recommendations. We think risperidone is poorly tolerated and should be used only as a last resort; that olanzapine is better than risperidone but will, in a majority of patients with PD, worsen motor function. We are optimistic, but not yet convinced, that quetiapine may prove to be as effective and better tolerated than clozapine. It will not require cumbersome monitoring because it does not induce a blood dyscrasia. We therefore recommend that DP be treated in the following manner. First, the anti-PD medications should be simplified and reduced as much as tolerated. We think, in general, side effects multiply more with increasing numbers of drugs than with drug dose, so that patients are more likely to tolerate a higher dose of levodopa than a lower dose of levodopa combined with other adjunctive anti-PD medications. In reducing anti-PD medications, we recommend tapering and stopping, if necessary, the drugs with the highest risk-to-benefit ratio first. Anticholinergics are stopped first, then selegiline, dopamine agonists, amantadine, and finally COMT inhibitors, which have no psychotomimetic action of their own. Finally, levodopa is reduced. Generally, a point is reached at which the anti-PD medications cannot be reduced without jeopardizing motor function. If psychosis persists at this point, then an antipsychotic is added. (ABS |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 3 | Psychiatr. Genet. 2000 Sep 10: 117-24 |
| PMID | 11204347 |
| Title | Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. |
| Abstract | A common functional polymorphism that results in a three- to four-fold difference in catechol-O-methyltransferase (COMT) enzyme activity has been related to psychiatric disorders such as ultra-ultra rapid cycling bipolar disorder, drug abuse and alcoholism (Lachman et al., 1996a; Karayiorgou et al., 1997; Vandenbergh et al., 1997; Papolos et al., 1998; Tiihonen et al., 1999). Several studies have also reported associations between the allele encoding the low enzyme activity COMT variant (L allele) and other-directed aggression (Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999) in schizophrenic and schizoaffective patients. The current study investigated whether the COMT L allele is also associated with suicide attempts in schizophrenic and schizoaffective patients. COMT genotypes were determined and history of suicide attempts was retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54). Significant associations were observed between COMT genotype and suicide; specifically, history of violent suicide attempts. The COMT L allele was more frequent in subjects who had attempted suicide by violent means. These associations were significant in males but not females. These findings support a common neurobiological substrate for self- and other-directed aggression, and suggest that catecholaminergic alterations may contribute to these behaviors in schizophrenic and schizoaffective patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 4 | Biol. Psychiatry 2000 Apr 47: 605-9 |
| PMID | 10745052 |
| Title | Ultradian rapid cycling in prepubertal and early adolescent bipolarity is not in transmission disequilibrium with val/met COMT alleles. |
| Abstract | Prepubertal children and early adolescents with bipolar disorders (PEA-BP) who participate in the ongoing study "Phenomenology and Course of Pediatric Bipolar Disorders" have a high prevalence of ultradian (within 24-hour periods) rapid cycling. Based on a case-control finding reported in bipolar (BP) adults of an association between rapid and ultradian rapid cycling with the low-activity allele of catechol-O-methyltransferase (l-COMT), study of linkage and linkage disequilibrium of l-COMT in the PEA-BP population seemed warranted. Genotypes on a subset of the larger PEA-BP sample, for whom trio blood collection was complete (i. e., probands and both of their biological parents), were used to perform transmission disequilibrium tests (TDTs). Diagnoses were established from a comprehensive battery that included WASH-U-KSADS (Washington University Kiddie Schedule for Affective Disorders and schizophrenia) given to both mothers and children and from consensus conferences. Probands with PEA-BP (N = 52) were 10.9 +/- 2.8 years old at index episode; had a mean age of BP onset at 8.0 +/- 3.8 years; were severely impaired, with a mean Children's Global Assessment Scale score of 44.5 +/- 8.9; and manifested the cardinal features of BP (84.6% had euphoric mood, 76.9% had grandiosity, and 57.7% had psychosis). Ultradian rapid cycling occurred in 75%. Genotyping of the single nucleotide polymorphism at COMT was performed using automated capillary electrophoresis single-strand conformational polymorphism with detection by laser-induced fluorescence. Transmission disequilibrium tests were not significant for preferential transmission of l-COMT for the ultradian rapid-cycling subgroup or for the entire PEA-BP sample. The lack of linkage disequilibrium between l-COMT and ultradian rapid cycling in the PEA-BP sample compared to reported findings of an association in case-control studies of adults is discussed in terms of age-specific developmentally relevant phenotypes, anticipatory mechanisms, and heterogeneity. Repeat TDT analyses after these PEA-BP probands reach their adult phenotypes will be informative. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 5 | Mol. Psychiatry 2000 Jan 5: 77-84 |
| PMID | 10673772 |
| Title | Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. |
| Abstract | Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family trios. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 6 | Psychiatr. Genet. 2000 Sep 10: 117-24 |
| PMID | 11204347 |
| Title | Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. |
| Abstract | A common functional polymorphism that results in a three- to four-fold difference in catechol-O-methyltransferase (COMT) enzyme activity has been related to psychiatric disorders such as ultra-ultra rapid cycling bipolar disorder, drug abuse and alcoholism (Lachman et al., 1996a; Karayiorgou et al., 1997; Vandenbergh et al., 1997; Papolos et al., 1998; Tiihonen et al., 1999). Several studies have also reported associations between the allele encoding the low enzyme activity COMT variant (L allele) and other-directed aggression (Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999) in schizophrenic and schizoaffective patients. The current study investigated whether the COMT L allele is also associated with suicide attempts in schizophrenic and schizoaffective patients. COMT genotypes were determined and history of suicide attempts was retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54). Significant associations were observed between COMT genotype and suicide; specifically, history of violent suicide attempts. The COMT L allele was more frequent in subjects who had attempted suicide by violent means. These associations were significant in males but not females. These findings support a common neurobiological substrate for self- and other-directed aggression, and suggest that catecholaminergic alterations may contribute to these behaviors in schizophrenic and schizoaffective patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 7 | Mol. Psychiatry 2000 Jan 5: 77-84 |
| PMID | 10673772 |
| Title | Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. |
| Abstract | Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family trios. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 8 | Biol. Psychiatry 2001 Dec 50: 825-44 |
| PMID | 11743939 |
| Title | Prefrontal neurons and the genetics of schizophrenia. |
| Abstract | This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing-the first plausible mechanism for a genetic effect on normal human cognition and risk for mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 9 | Br J Psychiatry 2001 Oct 179: 351-5 |
| PMID | 11581117 |
| Title | Aggressive behaviour in patients with schizophrenia is associated with catechol-O-methyltransferase genotype. |
| Abstract | Evidence exists for an association between aggression and schizophrenia. Although the aetiology of aggression is multifactorial, three studies have reported associations between polymorphisms of the catechol-O-methyltransferase (COMT) gene and aggression in schizophrenia. To replicate these findings in a larger sample using the Overt Aggression Scale (OAS). A sample of 180 people with DSM-IV schizophrenia were rated for aggression using the OAS. Kruskal-Wallis and contingency table analyses were applied to the OAS results. The high-activity homozygotes showed significantly higher scores of aggression, whereas the heterozygotes showed significantly lower scores. The odds ratio for aggression for the high-activity homozygotes was 2.07 (95% Cl=1.03-4.15), whereas that for the heterozygotes was 0.54 (95% Cl=0.30-1.00). CONCLUSIONS; The high-activity COMT homozygote confers a higher risk of recorded aggression in schizophrenia. Heterozygotes had a significantly lower risk, which may represent an example of heterosis/heterozygote advantage. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 10 | Psychiatry Res 2001 May 102: 87-90 |
| PMID | 11368843 |
| Title | No evidence for linkage between COMT and schizophrenia in a French population. |
| Abstract | Catechol-O-methyltransferase is a candidate in the predisposition to schizophrenia both because of its function and the position of its gene. A multipoint non-parametric linkage analysis and a transmission disequilibrium test were performed on 42 multiplex families genotyped for Pml I and Bcl I polymorphisms using two definitions of the affected phenotype. Neither linkage nor preferential transmission of any allele or haplotype was detected, failing to replicate previous positive findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 11 | Mol. Psychiatry 2001 Mar 6: 220-4 |
| PMID | 11317226 |
| Title | Family-based association studies of monoaminergic gene polymorphisms among North Indians with schizophrenia. |
| Abstract | Associations between schizophrenia and four candidate genes were tested among Indian patients with schizophrenia and their parents (DSM-IV criteria, n = 179 families). Polymorphisms within the genes encoding the serotonin 2A receptor (HT2A), tryptophan hydroxylase (TPH), catechol-O-methyl transferase (COMT) and dopamine transporter (DAT) were thus investigated. Two polymorphisms each were analyzed at HT2A and TPH, enabling haplotype-based analyses using the transmission disequilibrium test (TDT) for these genes. No significant associations were detected. Pooled analysis of samples like ours may be necessary to definitively exclude putative allelic associations at these loci. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 12 | Neuropsychobiology 2001 Jan 43: 11-4 |
| PMID | 11150892 |
| Title | Association analysis of a functional catechol-o-methyltransferase gene polymorphism in schizophrenic patients in Taiwan. |
| Abstract | The catechol-O-methyltransferase (COMT) gene was thought to be a candidate gene for schizophrenia because of its role in inactivating dopamine. This study examined the relationship between a functional polymorphism (val158met) of the COMT gene, schizophrenia and its associated behaviors. One hundred and ninety-eight Chinese schizophrenic patients and 188 controls were genotyped by polymerase chain reaction restriction fragment length polymorphism. Of the schizophrenic patients, 72 had a history of violence and 62 had a history of suicide attempts. The results failed to show significant association between val158met polymorphism and schizophrenia, violence or suicide. However, our results showed a significant difference in age at disease onset among different genotypes (F = 5.501, p = 0.005). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 13 | Biol. Psychiatry 2001 Dec 50: 825-44 |
| PMID | 11743939 |
| Title | Prefrontal neurons and the genetics of schizophrenia. |
| Abstract | This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing-the first plausible mechanism for a genetic effect on normal human cognition and risk for mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 14 | Neuropsychobiology 2001 Jan 43: 11-4 |
| PMID | 11150892 |
| Title | Association analysis of a functional catechol-o-methyltransferase gene polymorphism in schizophrenic patients in Taiwan. |
| Abstract | The catechol-O-methyltransferase (COMT) gene was thought to be a candidate gene for schizophrenia because of its role in inactivating dopamine. This study examined the relationship between a functional polymorphism (val158met) of the COMT gene, schizophrenia and its associated behaviors. One hundred and ninety-eight Chinese schizophrenic patients and 188 controls were genotyped by polymerase chain reaction restriction fragment length polymorphism. Of the schizophrenic patients, 72 had a history of violence and 62 had a history of suicide attempts. The results failed to show significant association between val158met polymorphism and schizophrenia, violence or suicide. However, our results showed a significant difference in age at disease onset among different genotypes (F = 5.501, p = 0.005). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 15 | Schizophr. Res. 2001 Dec 52: 161-5 |
| PMID | 11705709 |
| Title | Association of ZNF74 gene genotypes with age-at-onset of schizophrenia. |
| Abstract | Because of the manifestation of schizophrenic symptoms in individuals with interstitial deletions of chromosome 22q11.2, genes located in 22q11.2 are positional candidates for schizophrenia susceptibility. We genotyped five polymorphisms at D22S941, D22S944, D22S264, and D22S311, and the COMT gene in the common 3Mbp deletion region associated with 22q11 deletion syndrome in 300 Japanese schizophrenics and 300 controls and identified one patient with 22q11 deletion (Arinami et al., 2001). The results showed a trend of different genotypic distributions in D22S264 between patients with schizophrenia and controls (non-corrected p=0.04). Given this finding, we searched for mutations in the ZNF74 gene, which is located 11.2Kbp centromeric to D22S264. The ZNF74 gene is a member of the KRAB-zinc finger gene family and is expressed in the developing brain. Four polymorphisms, 1150T/C, IVS2a-40G/A, E/K46, and [K/N551;L/F552], were detected. The first three polymorphisms were in almost complete linkage disequilibrium. Case-control comparisons for these polymorphisms resulted in similar genotypic and allelic frequencies in patients and controls. The polymorphisms, however, were significantly associated with age-at-onset of schizophrenia (n<0.0001). Subsequent analyses in another Japanese schizophrenic population (n=169) confirmed an age-at-onset association (p<0.0001). These findings suggest that the ZNF74 gene plays a role as one of the modifying factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 16 | Psychiatr. Genet. 2001 Jun 11: 105-9 |
| PMID | 11525417 |
| Title | Catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association between symptomatology and prognosis. |
| Abstract | Catechol-O-methyltransferase (COMT) gene has long been implicated to play a role in the pathogenesis of schizophrenia. The aim of this study is to assess the relationship of schizophrenia and its subgroups with COMT gene polymorphism. We have attempted to evaluate a possible correlation between the severity and prognosis of the illness (the psychopathology of symptoms) and COMT gene polymorphisms. The study comprised 129 unrelated subjects who strictly met DSM-IV criteria for schizophrenia, and 65 healthy unrelated controls. All subjects were of Turkish origin. A clinical evaluation of all patients was accomplished by applying the Brief Psychiatric Rating Scale (BPRS) test. The analysis of COMT polymorphism was performed using the polymerase chain reaction technique. Regarding COMT gene polymorphisms, no statistically significant difference was found between schizophrenic patients and control subjects. However, within the schizophrenic group, the average of BPRS points of patients with the L/L genotype was significantly higher than those of the L/H and H/H genotypes (F = 6.25, degrees of freedom = 2, P = 0.003). Although no statistically significant difference was found between the duration of illness and COMT variations, a higher frequency of hospitalization was found in patients with the L/L genotype compared with other groups (t = 3.048, P = 0.003). In conclusion, the findings indicate that COMT gene polymorphisms were not statistically significant between patient and control groups. However, the patients with the L/L genotype may have much more severe clinical signs in Turkish schizophrenics. COMT variations, however, do not help to evaluate the susceptibility of the patients, but can help in the estimation of severity of clinical manifestations. Further studies are required to better understand the association of symptomatology of schizophrenia and other psychiatric disorders with COMT gene polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 17 | Proc. Natl. Acad. Sci. U.S.A. 2001 Jun 98: 6917-22 |
| PMID | 11381111 |
| Title | Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. |
| Abstract | Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 18 | Schizophr. Res. 2001 Dec 52: 161-5 |
| PMID | 11705709 |
| Title | Association of ZNF74 gene genotypes with age-at-onset of schizophrenia. |
| Abstract | Because of the manifestation of schizophrenic symptoms in individuals with interstitial deletions of chromosome 22q11.2, genes located in 22q11.2 are positional candidates for schizophrenia susceptibility. We genotyped five polymorphisms at D22S941, D22S944, D22S264, and D22S311, and the COMT gene in the common 3Mbp deletion region associated with 22q11 deletion syndrome in 300 Japanese schizophrenics and 300 controls and identified one patient with 22q11 deletion (Arinami et al., 2001). The results showed a trend of different genotypic distributions in D22S264 between patients with schizophrenia and controls (non-corrected p=0.04). Given this finding, we searched for mutations in the ZNF74 gene, which is located 11.2Kbp centromeric to D22S264. The ZNF74 gene is a member of the KRAB-zinc finger gene family and is expressed in the developing brain. Four polymorphisms, 1150T/C, IVS2a-40G/A, E/K46, and [K/N551;L/F552], were detected. The first three polymorphisms were in almost complete linkage disequilibrium. Case-control comparisons for these polymorphisms resulted in similar genotypic and allelic frequencies in patients and controls. The polymorphisms, however, were significantly associated with age-at-onset of schizophrenia (n<0.0001). Subsequent analyses in another Japanese schizophrenic population (n=169) confirmed an age-at-onset association (p<0.0001). These findings suggest that the ZNF74 gene plays a role as one of the modifying factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 19 | Schizophr. Res. 2001 Dec 52: 161-5 |
| PMID | 11705709 |
| Title | Association of ZNF74 gene genotypes with age-at-onset of schizophrenia. |
| Abstract | Because of the manifestation of schizophrenic symptoms in individuals with interstitial deletions of chromosome 22q11.2, genes located in 22q11.2 are positional candidates for schizophrenia susceptibility. We genotyped five polymorphisms at D22S941, D22S944, D22S264, and D22S311, and the COMT gene in the common 3Mbp deletion region associated with 22q11 deletion syndrome in 300 Japanese schizophrenics and 300 controls and identified one patient with 22q11 deletion (Arinami et al., 2001). The results showed a trend of different genotypic distributions in D22S264 between patients with schizophrenia and controls (non-corrected p=0.04). Given this finding, we searched for mutations in the ZNF74 gene, which is located 11.2Kbp centromeric to D22S264. The ZNF74 gene is a member of the KRAB-zinc finger gene family and is expressed in the developing brain. Four polymorphisms, 1150T/C, IVS2a-40G/A, E/K46, and [K/N551;L/F552], were detected. The first three polymorphisms were in almost complete linkage disequilibrium. Case-control comparisons for these polymorphisms resulted in similar genotypic and allelic frequencies in patients and controls. The polymorphisms, however, were significantly associated with age-at-onset of schizophrenia (n<0.0001). Subsequent analyses in another Japanese schizophrenic population (n=169) confirmed an age-at-onset association (p<0.0001). These findings suggest that the ZNF74 gene plays a role as one of the modifying factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 20 | Psychiatr. Genet. 2001 Jun 11: 105-9 |
| PMID | 11525417 |
| Title | Catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association between symptomatology and prognosis. |
| Abstract | Catechol-O-methyltransferase (COMT) gene has long been implicated to play a role in the pathogenesis of schizophrenia. The aim of this study is to assess the relationship of schizophrenia and its subgroups with COMT gene polymorphism. We have attempted to evaluate a possible correlation between the severity and prognosis of the illness (the psychopathology of symptoms) and COMT gene polymorphisms. The study comprised 129 unrelated subjects who strictly met DSM-IV criteria for schizophrenia, and 65 healthy unrelated controls. All subjects were of Turkish origin. A clinical evaluation of all patients was accomplished by applying the Brief Psychiatric Rating Scale (BPRS) test. The analysis of COMT polymorphism was performed using the polymerase chain reaction technique. Regarding COMT gene polymorphisms, no statistically significant difference was found between schizophrenic patients and control subjects. However, within the schizophrenic group, the average of BPRS points of patients with the L/L genotype was significantly higher than those of the L/H and H/H genotypes (F = 6.25, degrees of freedom = 2, P = 0.003). Although no statistically significant difference was found between the duration of illness and COMT variations, a higher frequency of hospitalization was found in patients with the L/L genotype compared with other groups (t = 3.048, P = 0.003). In conclusion, the findings indicate that COMT gene polymorphisms were not statistically significant between patient and control groups. However, the patients with the L/L genotype may have much more severe clinical signs in Turkish schizophrenics. COMT variations, however, do not help to evaluate the susceptibility of the patients, but can help in the estimation of severity of clinical manifestations. Further studies are required to better understand the association of symptomatology of schizophrenia and other psychiatric disorders with COMT gene polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 21 | Psychiatr. Genet. 2001 Jun 11: 105-9 |
| PMID | 11525417 |
| Title | Catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association between symptomatology and prognosis. |
| Abstract | Catechol-O-methyltransferase (COMT) gene has long been implicated to play a role in the pathogenesis of schizophrenia. The aim of this study is to assess the relationship of schizophrenia and its subgroups with COMT gene polymorphism. We have attempted to evaluate a possible correlation between the severity and prognosis of the illness (the psychopathology of symptoms) and COMT gene polymorphisms. The study comprised 129 unrelated subjects who strictly met DSM-IV criteria for schizophrenia, and 65 healthy unrelated controls. All subjects were of Turkish origin. A clinical evaluation of all patients was accomplished by applying the Brief Psychiatric Rating Scale (BPRS) test. The analysis of COMT polymorphism was performed using the polymerase chain reaction technique. Regarding COMT gene polymorphisms, no statistically significant difference was found between schizophrenic patients and control subjects. However, within the schizophrenic group, the average of BPRS points of patients with the L/L genotype was significantly higher than those of the L/H and H/H genotypes (F = 6.25, degrees of freedom = 2, P = 0.003). Although no statistically significant difference was found between the duration of illness and COMT variations, a higher frequency of hospitalization was found in patients with the L/L genotype compared with other groups (t = 3.048, P = 0.003). In conclusion, the findings indicate that COMT gene polymorphisms were not statistically significant between patient and control groups. However, the patients with the L/L genotype may have much more severe clinical signs in Turkish schizophrenics. COMT variations, however, do not help to evaluate the susceptibility of the patients, but can help in the estimation of severity of clinical manifestations. Further studies are required to better understand the association of symptomatology of schizophrenia and other psychiatric disorders with COMT gene polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 22 | Proc. Natl. Acad. Sci. U.S.A. 2001 Jun 98: 6917-22 |
| PMID | 11381111 |
| Title | Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. |
| Abstract | Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 23 | Mol. Psychiatry 2002 -1 7: 446-7 |
| PMID | 12082558 |
| Title | Family-based association studies of COMT gene polymorphisms and schizophrenia in the Chinese population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 24 | Psychiatry Res 2002 Dec 113: 49-57 |
| PMID | 12467945 |
| Title | Eye movement disturbances in schizophrenia and a polymorphism of catechol-O-methyltransferase gene. |
| Abstract | Previous studies suggested an association between the catechol-O-methyltransferase (COMT) Val/Met polymorphism and the performance on neuropsychological tests, measuring prefrontal function in schizophrenia. The aim of this study was to examine the relationship between this polymorphism and performance on oculomotoric tests in schizophrenic patients. The intensity of eye movement disturbances on fixation and smooth pursuit tests and the Val/Met polymorphism of COMT gene were studied in 117 schizophrenic patients (74 male and 43 female). In male schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was lower in subjects who had the Met/Met genotype, with significant difference compared to other genotypes. Also, a significantly higher frequency of the Met allele and the Met/Met genotype was found in male schizophrenic patients exhibiting a lower intensity of smooth pursuit disturbances, and a trend in this direction was observed for the intensity of fixation disturbances. No such relationship was found in female schizophrenic patients. The results obtained suggest that, in male schizophrenic patients the Met allele of the COMT Val/Met polymorphism may have an alleviating effect on eye movement disturbances. They also point to possible gender differences as to the role of COMT in brain function in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 25 | Am. J. Hum. Genet. 2002 Dec 71: 1296-302 |
| PMID | 12402217 |
| Title | A highly significant association between a COMT haplotype and schizophrenia. |
| Abstract | Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 26 | Nervenarzt 2002 Jul 73: 581-92; quiz 593-4 |
| PMID | 12212520 |
| Title | [Genetics of bipolar affective disorders. Current status of research for identification of susceptibility genes]. |
| Abstract | Bipolar affective disorder is a highly heritable condition, as evidenced by twin, family, and adoption studies. However, the mode of inheritance is complex and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged for several chromosomes, notably 3p12-p14, 4p16, 10q25-q26, and 12q23-q24. Three additional areas, 13q32-q33, 18p11-q11, and 22q12-q13, have shown linkage in regions that appear to overlap with linkage findings in schizophrenia. These chromosomal regions might harbour genes that contribute to the development of bipolar affective disorder. Recent candidate gene studies include some positive results for the serotonin transporter gene (5-HTT) on 17q11-q12 and the catechol-O-methyltransferase gene (COMT) on 22q11. New methods are being developed for linkage disequilibrium mapping and candidate gene approaches. One can be optimistic that over the next few years bipolar susceptibility genes will be identified. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 27 | Am. J. Med. Genet. 2002 Jul 114: 491-6 |
| PMID | 12116182 |
| Title | Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. |
| Abstract | Several lines of evidence suggest that psychosis is associated with altered dopaminergic neurotransmission. Dopamine is catabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk to schizophrenia. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the V158M COMT polymorphism in 346 DSMIV schizophrenics and 334 controls. We also genotyped the-287A > G COMT promoter polymorphism in 177 schizophrenics and 173 controls. No significant differences were found in allele or genotype frequencies between affecteds and controls for any of the polymorphisms. As both genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects but none was observed. Our data, therefore, do not support the hypothesis that genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 28 | Psychiatry Res 2002 Dec 113: 49-57 |
| PMID | 12467945 |
| Title | Eye movement disturbances in schizophrenia and a polymorphism of catechol-O-methyltransferase gene. |
| Abstract | Previous studies suggested an association between the catechol-O-methyltransferase (COMT) Val/Met polymorphism and the performance on neuropsychological tests, measuring prefrontal function in schizophrenia. The aim of this study was to examine the relationship between this polymorphism and performance on oculomotoric tests in schizophrenic patients. The intensity of eye movement disturbances on fixation and smooth pursuit tests and the Val/Met polymorphism of COMT gene were studied in 117 schizophrenic patients (74 male and 43 female). In male schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was lower in subjects who had the Met/Met genotype, with significant difference compared to other genotypes. Also, a significantly higher frequency of the Met allele and the Met/Met genotype was found in male schizophrenic patients exhibiting a lower intensity of smooth pursuit disturbances, and a trend in this direction was observed for the intensity of fixation disturbances. No such relationship was found in female schizophrenic patients. The results obtained suggest that, in male schizophrenic patients the Met allele of the COMT Val/Met polymorphism may have an alleviating effect on eye movement disturbances. They also point to possible gender differences as to the role of COMT in brain function in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 29 | Am. J. Med. Genet. 2002 Jul 114: 491-6 |
| PMID | 12116182 |
| Title | Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. |
| Abstract | Several lines of evidence suggest that psychosis is associated with altered dopaminergic neurotransmission. Dopamine is catabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk to schizophrenia. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the V158M COMT polymorphism in 346 DSMIV schizophrenics and 334 controls. We also genotyped the-287A > G COMT promoter polymorphism in 177 schizophrenics and 173 controls. No significant differences were found in allele or genotype frequencies between affecteds and controls for any of the polymorphisms. As both genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects but none was observed. Our data, therefore, do not support the hypothesis that genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 30 | Biol. Psychiatry 2002 Oct 52: 701-7 |
| PMID | 12372660 |
| Title | Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. |
| Abstract | Neurocognitive deficits are recognized as a cardinal feature of schizophrenia, but the determinants of these deficits remain unknown. Recent reports have suggested that a functional polymorphism, Val(158)Met in exon III of the catechol-O-methyltransferase gene, shares approximately 4% variance with performance on the Wisconsin Card Sorting Test. These findings led to suggestions that the catechol-O-methyltransferase polymorphism may exert its effects by modulating prefrontal dopamine function, but few other neurocognitive measures have been examined, leaving open questions about phenotypic specificity. We examined the effects of the catechol-O-methyltransferase Val(158)Met polymorphism in 58 individuals with chronic schizophrenia who completed a battery of 15 neurocognitive tests, which were reduced to four reliable neurocognitive domain scores. We examined the effects of genotype on these four domains and on global neurocognitive ability. The Met allele was associated with better performance in the Processing Speed and Attention domain, but not with other domain scores measuring executive and visuoperceptual functions, declarative verbal learning and memory, simple motor ability, or global neurocognitive function. Genotype shared approximately 11% of variance with Processing Speed and Attention scores, and approximately 2% of variance with Wisconsin Card Sorting Test scores. The findings provide independent support for the hypothesis that the catechol-O-methyltransferase Val(158)Met polymorphism influences neurocognitive function in schizophrenia, and suggest that the functional effects may be expressed on measures of Processing Speed and Attention. This information may prompt reconsideration of the "prefrontal dopamine" hypothesis and invites examination of a broader range of effects in efforts to refine the neurocognitive phenotype that is most relevant to variation in catechol-O-methyltransferase expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 31 | Mol. Psychiatry 2002 -1 7: 706-11 |
| PMID | 12192614 |
| Title | Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. |
| Abstract | The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 32 | Eur. Psychiatry 2002 Aug 17 Suppl 4: 355s-362s |
| PMID | 23573605 |
| Title | Schizophrenia, the prefrontal cortex, and a mechanism of genetic susceptibility. |
| Abstract | Information-processing in the prefrontal cortex is abnormal in patients with schizophrenia. From functional neuroimaging and other studies, it appears that neurons of the dorsolateral prefrontal cortex are effectors of core clinical and biological phenomena associated with the illness. Cognitive deficits qualitatively similar to those in patients with schizophrenia are also found in their healthy siblings and other relatives. The evidence for abnormal prefrontal function in healthy siblings suggests that the deficit in information-processing is part of the biology of genetic susceptibility. Therefore, genetic variations in human DNA that affect this kind of information-processing may contribute part of the genetic risk for the illness. COMT is an enzyme that is distributed widely throughout the brain, but seems to be uniquely relevant to how dopamine affects information-processing in the prefrontal cortex. There is a common variation in the genetic sequence of the COMT gene, which causes a dramatic change in its enzyme activity. In people with schizophrenia, in their healthy siblings, and also in normal controls, the COMT genotype predicts 4% of the variation in human executive cognition and working memory. We have thus identified a genetic mechanism in the human species that affects the efficiency and efficacy of information-processing in the prefrontal cortex. It is, also, a weak genetic risk factor for schizophrenia: in family studies, it increases the risk of schizophrenia by 50-80%. Prefrontal neuronal tuning may be a target for new drug development in the future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 33 | Eur Neuropsychopharmacol 2002 Aug 12: 299-303 |
| PMID | 12126868 |
| Title | Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia. |
| Abstract | Genetic polymorphism of catechol-O-methyltransferase (COMT), involved in the degradation of catecholamine neurotransmitters, has been investigated as a candidate for modifier of susceptibility to development of schizophrenia. To address this issue further, we carried out a study in Korean schizophrenic patients and controls. The study population consisted of 103 Korean inpatients diagnosed as schizophrenic and their 103 age and sex matched controls. The patients were divided into two groups on the basis of history of aggressive behavior, family history of schizophrenia and related disorders, and age at onset of the disease. The COMT genotypes were determined by a PCR based method. No statistically significant overall associations between the COMT genotypes and risk of schizophrenia were observed. However, subjects with at least one low activity associated COMT-L allele showed a tendency of elevated risk for schizophrenia (OR=1.7, 95% CI=0.9-3.1) compared with those homozygous for the high activity associated COMT-H alleles. Moreover, when cases were stratified by family history of schizophrenia, a significant combined effect was seen: the cases with concurrent family history of schizophrenia and the COMT-L allele containing genotypes had an almost 4-fold (OR=3.9, 95% CI=1.1-14.3) higher risk of schizophrenia compared to controls with the COMT-HH genotypes. Future studies with larger sample sizes are, however, needed to confirm this novel finding. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 34 | Maturitas 2002 Apr 41 Suppl 1: S55-64 |
| PMID | 11955795 |
| Title | Genetic modeling of estrogen metabolism as a risk factor of hormone-dependent disorders. |
| Abstract | Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and endometrial, prostate, and breast cancer. Available data indicate that the protective effect of a later age at menarche is limited to mutant CYP 17 allele carriers. Among women with the Polycystic Ovary (PCO) syndrome, mutant CYP 17 alleles are sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for breast cancer, advanced disease stage, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase (COMT) allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to estrogen metabolising genes as strong hereditary determinants of the susceptibility to benign and malignant conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 35 | Mol. Psychiatry 2002 -1 7: 706-11 |
| PMID | 12192614 |
| Title | Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. |
| Abstract | The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 36 | Eur Neuropsychopharmacol 2002 Aug 12: 299-303 |
| PMID | 12126868 |
| Title | Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia. |
| Abstract | Genetic polymorphism of catechol-O-methyltransferase (COMT), involved in the degradation of catecholamine neurotransmitters, has been investigated as a candidate for modifier of susceptibility to development of schizophrenia. To address this issue further, we carried out a study in Korean schizophrenic patients and controls. The study population consisted of 103 Korean inpatients diagnosed as schizophrenic and their 103 age and sex matched controls. The patients were divided into two groups on the basis of history of aggressive behavior, family history of schizophrenia and related disorders, and age at onset of the disease. The COMT genotypes were determined by a PCR based method. No statistically significant overall associations between the COMT genotypes and risk of schizophrenia were observed. However, subjects with at least one low activity associated COMT-L allele showed a tendency of elevated risk for schizophrenia (OR=1.7, 95% CI=0.9-3.1) compared with those homozygous for the high activity associated COMT-H alleles. Moreover, when cases were stratified by family history of schizophrenia, a significant combined effect was seen: the cases with concurrent family history of schizophrenia and the COMT-L allele containing genotypes had an almost 4-fold (OR=3.9, 95% CI=1.1-14.3) higher risk of schizophrenia compared to controls with the COMT-HH genotypes. Future studies with larger sample sizes are, however, needed to confirm this novel finding. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 37 | Mol. Psychiatry 2002 -1 7: 706-11 |
| PMID | 12192614 |
| Title | Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. |
| Abstract | The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 38 | Yi Chuan 2003 Nov 25: 652-4 |
| PMID | 15639952 |
| Title | [Association study of five pedigree with high incidence of schizophrenia]. |
| Abstract | This study is to explore the relationship between polymorphism of Catechol O-methyltransferase gene and schizophrenia. Search for a gene predisposing to schizophrenia in the Han nationality in China. Five pedigrees with high incidence of schizophrenia were studied by polymerize chain reaction(PCR) and restriction fragment length polymorphism(RFLP) technique. Statistics analysis of the transmission/disequilibrium test (TDT) showed that the COMT gene is associated with schizophrenia in the five pedigree with high incidence schizophrenia(P=0.0455). The results suggest that there might have a schizophrenia liability gene on 22 chromosome (22q11.2) in our studied pedigrees. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 39 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 47-50 |
| PMID | 12815739 |
| Title | Association between Val108/158 Met polymorphism of the COMT gene and schizophrenia. |
| Abstract | schizophrenia is a complex disorder with a multifactorial polygenic inheritance with several genes conferring susceptibility at many genetic locations, each with a small effect. An attractive candidate gene for schizophrenia is the catechol-O-methyltransferase (COMT) gene, which is a modulator of dorsolateral prefrontal cortical function. A missense G to A mutation in this gene that results in a substitution of Methionine (Met) for Valine (Val) at codon 108/158 (Val(108/158) Met) has recently been identified in association to schizophrenia. We compared allele frequencies of the variant Val allele between 96 schizophrenia cases and 80 normal controls. We selected controls from a similar pool to cases in ethnicity and gender. The frequency of the Val allele was significantly higher in schizophrenia cases compared to controls (0.620 vs. 0.506; P = 0.043). Calculation of the population attributable risk suggests that the Val allele accounts for as much as 23% of schizophrenia in this population (range: 3-38%). These results provide support for a role of this variant in the etiopathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 40 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 35-9 |
| PMID | 12815736 |
| Title | Relationship between catechol-O-methyltransferase polymorphism and treatment-resistant schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) plays a crucial role in the regulation of central dopaminergic systems. We examined the allelic association of a functional polymorphism of the COMT gene with the clinical manifestations and the response to antipsychotics of 100 schizophrenic patients and 201 healthy controls from the general Japanese population. No statistically significant difference was observed in the allele and genotype frequencies between the schizophrenic patients and the healthy controls. The daily neuroleptic dosage that patients received during their maintenance therapy was significantly higher in patients with the L/L genotype than in the other patients (P < 0.05). The present results suggest that the presence of the COMT genotype does not help in evaluating the susceptibility to the development of schizophrenia, but that it may help in the estimation of treatment-resistant features of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 41 | Eur. Psychiatry 2003 Mar 18: 77-81 |
| PMID | 12711403 |
| Title | Tardive dyskinesia is not associated with the polymorphisms of 5-HT2A receptor gene, serotonin transporter gene and catechol-o-methyltransferase gene. |
| Abstract | The pathophysiology of tardive dyskinesia (TD) is not completely understood.Aim. - To assess the relationship of TD with 5-HT2A receptor gene, serotonin transporter gene (5 HTT), and catechol-o-methyltransferase (COMT) gene polymorphisms. Our study comprised 111 unrelated subjects who strictly met DSM-IV criteria for schizophrenia and 32 TD, and 79 healthy unrelated controls; all the subjects were of Turkish origin. The analyses of 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were performed using polymerase chain reaction (PCR) technique. The polymorphisms of these genes were not significantly different between the schizophrenic patients, TD and control subjects. Our findings indicated that 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were similar in schizophrenia with non-TD, schizophrenia with TD, and healthy controls. These polymorphisms, though, do not help to evaluate the susceptibility to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 42 | J. Neurosci. 2003 Mar 23: 2008-13 |
| PMID | 12657658 |
| Title | Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. |
| Abstract | A functional polymorphism in the gene for catechol-O-methyltransferase (COMT) has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans, probably by affecting prefrontal dopamine signaling. The COMT valine allele, associated with relatively poor prefrontal function, is also a gene that may increase risk for schizophrenia. Although poor performance on executive cognitive tasks and abnormal prefrontal function are characteristics of schizophrenia, so is psychosis, which has been related to excessive presynaptic dopamine activity in the striatum. Studies in animals have shown that diminished prefrontal dopamine neurotransmission leads to upregulation of striatal dopamine activity. We measured tyrosine hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain and found that the COMT valine allele is also associated with increased TH gene expression, especially in neuronal populations that project to the striatum. This indicates that COMT genotype is a heritable aspect of dopamine regulation and it further explicates the mechanism by which the COMT valine allele increases susceptibility for psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 43 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Feb 20: 69-71 |
| PMID | 12579508 |
| Title | [Associations between six functional genes and schizophrenia]. |
| Abstract | To assess the associations between schizophrenia and six functional genes: dopamine D2 receptor gene (DRD2), dopamine D4 receptor gene (DRD4), 5-hydroxytryptamine 2A receptor gene (5-HT2A), 5-HT6 receptor gene (5-HT6), catechol-O-methyltransferase gene (COMT) and dopamine transporter gene (DAT1). With the techniques of Amp-RFLP and Amp-FLP, association analysis was made between schizophrenia and the six genes in 67 schizophrenic patients from Chinese Han population. (1) Neither genotypes nor alleles of DRD2, 5-HT2A, 5-HT6 and COMT gene showed significant differences between patients and controls (P>0.05). (2) Six repeats (6R) in DRD4 gene, the allele of 480 bp and the genotype of 480/520 in DAT1 gene were found to be of significant differences between the two groups (P<0.05). (3) Only one negative association was observed between the 480 bp allele of DAT1 gene and schizophrenia (OR=0.441, 95% CI:0.202-0.963, Z=2.05, P<0.05). The 480 bp allele of DAT1 gene is negatively associated with schizophrenia in Chinese Han population, which stands for the dopamine hypothesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 44 | Neurosci. Lett. 2003 Feb 338: 123-6 |
| PMID | 12566168 |
| Title | Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females. |
| Abstract | Using the Wisconsin Card Sorting Test, it has been determined, that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect dopamine metabolism, is associated with prefrontal cognitive function. This study of a cohort of 120 healthy young Chinese females attempted to utilize P300 event-related potentials to replicate this finding and to test the relationship between this COMT polymorphism and cortical physiology. The results demonstrate that subjects bearing the Met/Met homozygote have significantly lower mean P300 latencies than do analogs bearing the Val allele. A significant association between this COMT polymorphism and perseverative errors was not demonstrated in the Wisconsin Card Sorting Test, however. We suggest that, although the COMT Val158Met genetic polymorphism may play a role in cognitive function, ethnicity and testing method may affect the association. Since statistical relationships between P300 components and both the COMT genetic polymorphism and schizophrenic disorders have been demonstrated, it seems reasonable to suggest that this COMT genetic variant may affect the P300 abnormality in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 45 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 35-9 |
| PMID | 12815736 |
| Title | Relationship between catechol-O-methyltransferase polymorphism and treatment-resistant schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) plays a crucial role in the regulation of central dopaminergic systems. We examined the allelic association of a functional polymorphism of the COMT gene with the clinical manifestations and the response to antipsychotics of 100 schizophrenic patients and 201 healthy controls from the general Japanese population. No statistically significant difference was observed in the allele and genotype frequencies between the schizophrenic patients and the healthy controls. The daily neuroleptic dosage that patients received during their maintenance therapy was significantly higher in patients with the L/L genotype than in the other patients (P < 0.05). The present results suggest that the presence of the COMT genotype does not help in evaluating the susceptibility to the development of schizophrenia, but that it may help in the estimation of treatment-resistant features of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 46 | Eur. Psychiatry 2003 Mar 18: 77-81 |
| PMID | 12711403 |
| Title | Tardive dyskinesia is not associated with the polymorphisms of 5-HT2A receptor gene, serotonin transporter gene and catechol-o-methyltransferase gene. |
| Abstract | The pathophysiology of tardive dyskinesia (TD) is not completely understood.Aim. - To assess the relationship of TD with 5-HT2A receptor gene, serotonin transporter gene (5 HTT), and catechol-o-methyltransferase (COMT) gene polymorphisms. Our study comprised 111 unrelated subjects who strictly met DSM-IV criteria for schizophrenia and 32 TD, and 79 healthy unrelated controls; all the subjects were of Turkish origin. The analyses of 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were performed using polymerase chain reaction (PCR) technique. The polymorphisms of these genes were not significantly different between the schizophrenic patients, TD and control subjects. Our findings indicated that 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were similar in schizophrenia with non-TD, schizophrenia with TD, and healthy controls. These polymorphisms, though, do not help to evaluate the susceptibility to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 47 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Feb 20: 69-71 |
| PMID | 12579508 |
| Title | [Associations between six functional genes and schizophrenia]. |
| Abstract | To assess the associations between schizophrenia and six functional genes: dopamine D2 receptor gene (DRD2), dopamine D4 receptor gene (DRD4), 5-hydroxytryptamine 2A receptor gene (5-HT2A), 5-HT6 receptor gene (5-HT6), catechol-O-methyltransferase gene (COMT) and dopamine transporter gene (DAT1). With the techniques of Amp-RFLP and Amp-FLP, association analysis was made between schizophrenia and the six genes in 67 schizophrenic patients from Chinese Han population. (1) Neither genotypes nor alleles of DRD2, 5-HT2A, 5-HT6 and COMT gene showed significant differences between patients and controls (P>0.05). (2) Six repeats (6R) in DRD4 gene, the allele of 480 bp and the genotype of 480/520 in DAT1 gene were found to be of significant differences between the two groups (P<0.05). (3) Only one negative association was observed between the 480 bp allele of DAT1 gene and schizophrenia (OR=0.441, 95% CI:0.202-0.963, Z=2.05, P<0.05). The 480 bp allele of DAT1 gene is negatively associated with schizophrenia in Chinese Han population, which stands for the dopamine hypothesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 48 | Neurosci. Lett. 2003 Feb 338: 123-6 |
| PMID | 12566168 |
| Title | Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females. |
| Abstract | Using the Wisconsin Card Sorting Test, it has been determined, that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect dopamine metabolism, is associated with prefrontal cognitive function. This study of a cohort of 120 healthy young Chinese females attempted to utilize P300 event-related potentials to replicate this finding and to test the relationship between this COMT polymorphism and cortical physiology. The results demonstrate that subjects bearing the Met/Met homozygote have significantly lower mean P300 latencies than do analogs bearing the Val allele. A significant association between this COMT polymorphism and perseverative errors was not demonstrated in the Wisconsin Card Sorting Test, however. We suggest that, although the COMT Val158Met genetic polymorphism may play a role in cognitive function, ethnicity and testing method may affect the association. Since statistical relationships between P300 components and both the COMT genetic polymorphism and schizophrenic disorders have been demonstrated, it seems reasonable to suggest that this COMT genetic variant may affect the P300 abnormality in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 49 | Eur. J. Pharmacol. 2003 Nov 480: 177-84 |
| PMID | 14623361 |
| Title | The genetics of schizophrenia: glutamate not dopamine? |
| Abstract | The major targets of current drugs used in mental health, such as neurotransmitter receptors and transporters, are based on serendipitous findings from several decades ago, and there is currently a severe drought of new drug targets. There is a pressing need for novel drugs, and much hope has been placed on the use of molecular genetics to help define them. However, despite evidence for a genetic basis to schizophrenia stretching back for over a century, and a heritability of about 80%, the identification of susceptibility genes has been an uphill struggle. Candidate gene studies, which have generally focussed on obvious candidates from the dopamine and serotonin systems, as well as genes involved in brain development, have not generally been successful, although meta-analysis indicates that the dopamine D3 receptor gene (DRD3) and the serotonin receptor gene type 2A (HTR2A) may have a very small influence on risk. Linkage analysis has provided robust evidence of genetic loci, for example, on chromosomes 8p, 13q and 22q, and also implies shared genetic aetiology with bipolar disorder. The identification of these loci together with advances in genetic technology, especially the characterisation of polymorphisms, the understanding of haplotypes and the development of statistical methods, has lead to the identification of several plausible susceptibility genes, including neuregulin 1, proline dehydrogenase and dysbindin. Interestingly, these genes point more towards a role for the glutamate pathway rather than the dopamine pathway in schizophrenia. We have attempted to replicate some of these findings in schizophrenic patients from SW China, and we find significant association with a novel neuregulin 1 haplotype, with proline dehydrogenase polymorphisms, but not with catechol-O-methyltransferase (COMT). The replication of neuregulin 1 association on chromosome 8p by several investigators is the most convincing to date, and the presence of a syndrome similar to dementia praecox of 8p linked families, and the lack of linkage of bipolar disorder to this region is a testament to the ideas of Kraepelin more than 100 years ago. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 50 | Pharmacogenomics J. 2003 -1 3: 356-61 |
| PMID | 14610521 |
| Title | Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. |
| Abstract | Risperidone is a widely used atypical antipsychotic with certain advantages over typical antipsychotics. Although variations in the efficacy of treatment with risperidone have been observed, no specific predictable marker has been identified as of yet. In all, 73 Japanese patients with schizophrenia were given risperidone for 8 weeks, and clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Six candidate polymorphisms (HTR2A -1438G>A, 102T>C, H452Y; DRD2 -141delC, Taq I A; COMT V158M) were genotyped. The diplotype configuration for each individual was estimated by the maximum-likelihood method. Multiple linear regressions were used to analyze the effects of these haplotypes/genotype and other prognostic factors on PANSS scale performance. After adjustment for the effects of patient-related variables, HTR2A diplotype and COMT genotype, as well as other potential prognostic factors, did not significantly influence the clinical performance. A DRD2 haplotype tended to correlate with better clinical performance. Compared with patients who had Ins-A2/Ins-A2 diplotype (n=25), PANSS total scores of patients with Ins-A2/Del-A1 diplotype (n=10) showed 40% greater improvement (P=0.03). The PANSS total scores of patients with HTR2A A-T/A-T diplotype (n=22) tended to show 15% worse improvement compared with A-T/G-C diplotype (n=33) (P=0.06). These results should be treated with caution because of limitations due to small sample size, heterogeneity of patients with respect to past antipsychotic use history, and no correction for multiple corrections. However, the present findings generate important hypotheses in a sample of Japanese schizophrenia patients that may lay the foundation for future pharmacogenomics investigations in other populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 51 | Arch. Gen. Psychiatry 2003 Sep 60: 889-96 |
| PMID | 12963670 |
| Title | Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. |
| Abstract | Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol-O-methyltransferase (COMT) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 52 | Hum. Mol. Genet. 2003 Oct 12 Spec No 2: R125-33 |
| PMID | 12952866 |
| Title | Recent advances in the genetics of schizophrenia. |
| Abstract | The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. As a result, several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34 where single studies have achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. Other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for COMT, RGS4 and G72 is promising but not yet persuasive. While it is essential that further replications are established, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that genetic research is poised to deliver crucial insights into the nature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 53 | Biol. Psychiatry 2003 Jul 54: 40-8 |
| PMID | 12842307 |
| Title | Association of the G1947A COMT (Val(108/158)Met) gene polymorphism with prefrontal P300 during information processing. |
| Abstract | A common functional polymorphism, G1947A, of the catechol-O-methyltransferase (COMT) enzyme has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function. An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude. The P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated. We observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients. The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 54 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 29-34 |
| PMID | 12815735 |
| Title | Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. |
| Abstract | We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O-methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 55 | Am. J. Hum. Genet. 2003 Jul 73: 152-61 |
| PMID | 12802784 |
| Title | A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. |
| Abstract | The gene encoding catechol-O-methyltransferase (COMT) is a strong candidate for schizophrenia susceptibility, owing to the role of COMT in dopamine metabolism, and the location of the gene within the deleted region in velocardiofacial syndrome, a disorder associated with high rates of schizophrenia. Recently, a highly significant association was reported between schizophrenia and a COMT haplotype in a large case-control sample (Shifman et al. 2002). In addition to a functional valine-->methionine (Val/Met) polymorphism, this haplotype included two noncoding single-nucleotide polymorphisms (SNPs) at either end of the COMT gene. Given the role of COMT in dopamine catabolism and that deletion of 22q11 (containing COMT) is associated with schizophrenia, we postulated that the susceptibility COMT haplotype is associated with low COMT expression. To test this hypothesis, we have applied quantitative measures of allele-specific expression using mRNA from human brain. We demonstrate that COMT is subject to allelic differences in expression in human brain and that the COMT haplotype implicated in schizophrenia (Shifman et al. 2002) is associated with lower expression of COMT mRNA. We also show that the 3' flanking region SNP that gave greatest evidence for association with schizophrenia in that study is transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. Our results indicate that COMT variants other than the Val/Met change are of functional importance in human brain and that the haplotype implicated in schizophrenia susceptibility is likely to exert its effect, directly or indirectly, by down-regulating COMT expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 56 | Neuropsychopharmacology 2003 Aug 28: 1521-30 |
| PMID | 12799619 |
| Title | Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia. |
| Abstract | Human prefrontal cortical neurons express catechol O-methyltransferase (COMT), an enzyme that inactivates the neurotransmitter dopamine. A functional polymorphism of COMT, Val(108/158) Met, affects prefrontal function, and the high-activity Val allele has been reported to be a genetic risk factor for schizophrenia. We used in situ hybridization histochemistry to measure mRNA levels of COMT in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia (N=14) and of normal controls (N=15). While the groups did not differ in terms of mean level of COMT mRNA, there was a significantly different laminar pattern of COMT mRNA expression in pyramidal neurons (F=2.68, df=4,108, P <0.04); patients with schizophrenia had relatively lower levels in the superficial (II/III) layers and higher levels in the intermediate/deep (IV/V) layers (P&<0.01), while in controls, the expression was homogeneous across layers. Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val(108/158) Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism. The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 57 | Eur Neuropsychopharmacol 2003 May 13: 147-51 |
| PMID | 12729939 |
| Title | Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. |
| Abstract | Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 58 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 35-9 |
| PMID | 12707935 |
| Title | Family-based and case-control study of catechol-O-methyltransferase in schizophrenia among Palestinian Arabs. |
| Abstract | COMT is a ubiquitous enzyme crucial to catechol metabolism. The molecular basis of COMT thermolability, that leads to three to fourfold differences in enzyme activity, is due to a substitution of valine with methionine in the Val158/108Met polymorphism. Of special interest is the role of this gene in major psychoses especially since a microdeletion (22q11) containing the COMT gene (velo-cardio-facial syndrome) also carries with it several types of behavioral disorders, including an increased prevalence of schizophrenia. Almost 20 genetic studies have examined the role of COMT in schizophrenia with ambiguous results. Towards clarifying the role of this polymorphism in conferring risk for psychosis, we examined a large group of culturally and ethnically akin Palestinian Arab schizophrenic triads (N = 276) using both a case-control and family-based study. In 194 informative triads with at least one heterozygote parent, no preferential transmission of either COMT allele was observed in this sample (TDT statistic chi-square = 0.14 NS; 131 COMT valine alleles were transmitted and 125 alleles not transmitted). However, using a case-control design a significant increase (Likelihood ratio = 3.935, P = 0.047) in the valine allele was observed in the group of schizophrenic patients (N = 276) compared to an ethnically matched control group (N = 77). The association was stronger in female patients (P = 0.012) similar to other studies showing that some COMT behavioral effects are gender sensitive. In summary, by case-control design but not by a family-based study, there is a weak effect in female patients of the high activity COMT allele in conferring risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 59 | Am J Psychiatry 2003 Mar 160: 469-76 |
| PMID | 12611827 |
| Title | Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. |
| Abstract | There is strong evidence for a genetic contribution to schizophrenia, but efforts to identify susceptibility genes have been largely unsuccessful because of the low power of individual studies. The authors' goal was to evaluate the collective evidence for an association between the Val158/108Met polymorphism of the catechol O-methyltransferase (COMT) gene and schizophrenia. They performed separate meta-analyses of existing case-control and family-based association studies. Overall, case-control studies showed no indication of an association between either allele and schizophrenia, and family-based studies found modest evidence implicating the Val allele in schizophrenia risk. The pooled analyses of studies from diverse geographical regions may have obscured ethnic differences in patterns of genetic risk for schizophrenia. Stratification of the studies by ethnicity of the subjects yielded evidence for an association with the Val allele in case-control studies of European samples and, especially, in family-based studies of European samples. Case-control and family-based studies of Asian samples produced mixed results and, overall, little evidence for association. The results of the two types of association studies diverged somewhat, but the evidence from the family-based studies, although based on fewer reports, may be more accurate. The Val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry, but the influence of this polymorphism on risk in Asian populations remains unclear. These results call for more family-based studies to confirm the association between COMT and schizophrenia in European samples and to clarify its contribution to risk in Asian samples. They also suggest that case-control studies should use methods of genomic control to avoid being confounded by population stratification. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 60 | Eur. J. Pharmacol. 2003 Nov 480: 177-84 |
| PMID | 14623361 |
| Title | The genetics of schizophrenia: glutamate not dopamine? |
| Abstract | The major targets of current drugs used in mental health, such as neurotransmitter receptors and transporters, are based on serendipitous findings from several decades ago, and there is currently a severe drought of new drug targets. There is a pressing need for novel drugs, and much hope has been placed on the use of molecular genetics to help define them. However, despite evidence for a genetic basis to schizophrenia stretching back for over a century, and a heritability of about 80%, the identification of susceptibility genes has been an uphill struggle. Candidate gene studies, which have generally focussed on obvious candidates from the dopamine and serotonin systems, as well as genes involved in brain development, have not generally been successful, although meta-analysis indicates that the dopamine D3 receptor gene (DRD3) and the serotonin receptor gene type 2A (HTR2A) may have a very small influence on risk. Linkage analysis has provided robust evidence of genetic loci, for example, on chromosomes 8p, 13q and 22q, and also implies shared genetic aetiology with bipolar disorder. The identification of these loci together with advances in genetic technology, especially the characterisation of polymorphisms, the understanding of haplotypes and the development of statistical methods, has lead to the identification of several plausible susceptibility genes, including neuregulin 1, proline dehydrogenase and dysbindin. Interestingly, these genes point more towards a role for the glutamate pathway rather than the dopamine pathway in schizophrenia. We have attempted to replicate some of these findings in schizophrenic patients from SW China, and we find significant association with a novel neuregulin 1 haplotype, with proline dehydrogenase polymorphisms, but not with catechol-O-methyltransferase (COMT). The replication of neuregulin 1 association on chromosome 8p by several investigators is the most convincing to date, and the presence of a syndrome similar to dementia praecox of 8p linked families, and the lack of linkage of bipolar disorder to this region is a testament to the ideas of Kraepelin more than 100 years ago. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 61 | Arch. Gen. Psychiatry 2003 Sep 60: 889-96 |
| PMID | 12963670 |
| Title | Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. |
| Abstract | Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol-O-methyltransferase (COMT) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 62 | Biol. Psychiatry 2003 Jul 54: 40-8 |
| PMID | 12842307 |
| Title | Association of the G1947A COMT (Val(108/158)Met) gene polymorphism with prefrontal P300 during information processing. |
| Abstract | A common functional polymorphism, G1947A, of the catechol-O-methyltransferase (COMT) enzyme has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function. An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude. The P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated. We observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients. The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 63 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 29-34 |
| PMID | 12815735 |
| Title | Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. |
| Abstract | We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O-methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 64 | Eur Neuropsychopharmacol 2003 May 13: 147-51 |
| PMID | 12729939 |
| Title | Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. |
| Abstract | Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 65 | Eur Neuropsychopharmacol 2003 May 13: 147-51 |
| PMID | 12729939 |
| Title | Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. |
| Abstract | Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 66 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 35-9 |
| PMID | 12707935 |
| Title | Family-based and case-control study of catechol-O-methyltransferase in schizophrenia among Palestinian Arabs. |
| Abstract | COMT is a ubiquitous enzyme crucial to catechol metabolism. The molecular basis of COMT thermolability, that leads to three to fourfold differences in enzyme activity, is due to a substitution of valine with methionine in the Val158/108Met polymorphism. Of special interest is the role of this gene in major psychoses especially since a microdeletion (22q11) containing the COMT gene (velo-cardio-facial syndrome) also carries with it several types of behavioral disorders, including an increased prevalence of schizophrenia. Almost 20 genetic studies have examined the role of COMT in schizophrenia with ambiguous results. Towards clarifying the role of this polymorphism in conferring risk for psychosis, we examined a large group of culturally and ethnically akin Palestinian Arab schizophrenic triads (N = 276) using both a case-control and family-based study. In 194 informative triads with at least one heterozygote parent, no preferential transmission of either COMT allele was observed in this sample (TDT statistic chi-square = 0.14 NS; 131 COMT valine alleles were transmitted and 125 alleles not transmitted). However, using a case-control design a significant increase (Likelihood ratio = 3.935, P = 0.047) in the valine allele was observed in the group of schizophrenic patients (N = 276) compared to an ethnically matched control group (N = 77). The association was stronger in female patients (P = 0.012) similar to other studies showing that some COMT behavioral effects are gender sensitive. In summary, by case-control design but not by a family-based study, there is a weak effect in female patients of the high activity COMT allele in conferring risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 67 | Neurosci. Lett. 2004 Nov 370: 127-9 |
| PMID | 15488308 |
| Title | Catechol-O-methyltransferase gene polymorphism is associated with risk of psychosis in Alzheimer Disease. |
| Abstract | There is emerging evidence that psychosis in Alzheimer Disease (AD) represents a clinically relevant phenotype with a distinct biological process. It has been reported that a functional polymorphism of the catechol-O-methyltransferase (COMT) gene predisposes to an increased risk for schizophrenia and likely to psychosis susceptibility. Aim of this study was to evaluate functional COMT genetic variation as a risk factor for psychosis in Alzheimer Disease. One hundred eighty-one AD patients and 208 age-matched controls underwent clinical and neuropsychological examination, behavioural and psychiatric disturbances evaluation, and ApoE and COMT genotyping. The distribution of COMT genotypes did not significantly differ in AD compared to controls. Among patients with psychosis (32.6%), 88.1% were COMT*H carriers (COMT H/H or COMT H/L, p < .01). The Odds Ratio (OR) for risk of psychosis in COMT*H carriers was 2.66 (confidence interval, CI 95%: 1.6-6.62), taking into account possible confounding factors. A comparable influence of COMT polymorphism on psychosis over the course of the disease was reported. These findings suggest that COMT polymorphism influences on the risk of psychosis since the early stages, and claims for the possibility to identify distinct phenotypes on genetic basis among AD patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 68 | Psychiatr Prax 2004 Nov 31 Suppl 1: S58-60 |
| PMID | 15570503 |
| Title | [No evidence for gender-specific sharing of COMT alleles in schizophrenia]. |
| Abstract | Catechol-o-methyltransferase (COMT) plays a major role in dopamine metabolism and has been the object of extensive investigations in subjects affected by schizophrenia. Interest in the enzyme has grown in recent years following positive linkage findings for schizophrenia in the chromosomal region surrounding the COMT gene locus on 22q. In several studies, a gender-specific association of COMT polymorphisms with schizophrenia has been reported and has given rise to speculations on transmission ratio distortions. The present investigation addressed allelic distributions in 307 men and women with respect to the rs165599 A > G polymorphism. No evidence was obtained for gender bias in allelic patterns, nor did we observe association with schizophrenia (p = 0.4). While studies involving same-sex siblings are lacking, gender-specific sharing of alleles does not appear to be a consistent feature of the COMT variant investigated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 69 | Am J Psychiatry 2004 Dec 161: 2320-2 |
| PMID | 15569909 |
| Title | Catechol O-methyltransferase polymorphism and eye tracking in schizophrenia: a preliminary report. |
| Abstract | This study examined associations between functional polymorphism (Val(108/158) Met) in the catechol O-methyltransferase (COMT) gene and eye tracking measures in schizophrenia. Predictive pursuit and closed-loop gains of 62 patients with schizophrenia and 53 healthy comparison subjects with Val-Val, Val-Met, and Met-Met genotypes were compared. There was a significant diagnosis-by-genotype interaction: patients with the Met-Met genotype showed poor predictive pursuit. The Met-Met genotype in healthy subjects was associated with significantly higher predictive pursuit gain values than the Val-Val genotype in healthy subjects. The COMT genotype explained about 10% of the variance in each group's predictive pursuit performance. These preliminary data suggest that the COMT gene is associated with predictive eye tracking performance in healthy subjects. Predictive pursuit abnormality in schizophrenia is not attributable to the Val allele. These findings suggest a complex interaction with other etiological factors (e.g., another gene), and/or with prefrontal cortical dopaminergic activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 70 | Am J Psychiatry 2004 Sep 161: 1700-2 |
| PMID | 15337663 |
| Title | Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. |
| Abstract | The 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) is associated with attentional problems and executive dysfunction, and is one of the highest known risk factors for schizophrenia. These behavioral manifestations of 22q11.2 deletion syndrome could result from haploinsufficiency of the catechol O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype as a predictor of prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Patients with confirmed 22q11.2 deletions (N=44) underwent neurocognitive testing following Val(158)Met genotyping (Met hemizygous: N=16; Val hemizygous: N=28). Analyses of covariance revealed that Met-hemizygous patients performed significantly better on a composite measure of executive function (comprising set-shifting, verbal fluency, attention, and working memory) than did Val-hemizygous patients. These data are consistent with those of previous studies in normal individuals, suggesting that a functional genetic polymorphism in the 22q11 region may influence prefrontal cognition in individuals with COMT haploinsufficiency. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 71 | Curr Psychiatry Rep 2004 Aug 6: 303-12 |
| PMID | 15260947 |
| Title | The genes for schizophrenia: finally a breakthrough? |
| Abstract | A number of susceptibility genes for schizophrenia have recently been identified. They have engendered excitement because replicate studies have attained greater consistency than in the past. In this review, we outline gene mapping methods, and briefly review their strengths and challenges. We also evaluate peer-reviewed genetic association studies that have implicated six selected genes: catechol-O-methyl transferase (COMT), neuregulin 1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signaling 4 (RGS4), and G72 and D-amino-acid oxidase (DAAO). The available supporting evidence is variable. Though credible evidence is available for all of these genes, it is strongest for NRG1 and DTNBP1. Further studies, particularly exhaustive analyses of all polymorphisms at each locus, meta-analyses, and investigations of the likely function of risk alleles (variants) are desirable. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 72 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 61-4 |
| PMID | 15211633 |
| Title | COMT: a common susceptibility gene in bipolar disorder and schizophrenia. |
| Abstract | A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 73 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 19-20 |
| PMID | 15211623 |
| Title | Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia. |
| Abstract | Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 74 | Am J Psychiatry 2004 Jun 161: 1110-2 |
| PMID | 15169701 |
| Title | New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. |
| Abstract | Using a sample of sibling pairs discordant for psychosis, the authors attempted to replicate the findings of previous studies suggesting that the functional genetic polymorphism Val158Met in the catechol O-methyltransferase (COMT) gene influences prefrontal cognitive function and increases the risk for schizophrenia. Eighty-nine sibling pairs discordant for psychosis were genotyped for this polymorphism and were assessed with the Wisconsin Card Sorting Test, a measure of prefrontal function. Additionally, the preferential transmission of alleles for this polymorphism was analyzed in a sample of 89 nuclear families in order to examine the genetic association. In the healthy siblings, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (i.e., fewer perseverative errors with higher number of methionine alleles). However, this association was not observed in patients. Furthermore, no evidence of genetic association with psychosis was detected. These results seem to confirm the role of COMT genotype in the modulation of executive functions related to frontal lobe function in healthy individuals but not in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 75 | Neuropsychobiology 2004 -1 49: 196-200 |
| PMID | 15118357 |
| Title | Association study of a functional catechol-O-methyltransferase genetic polymorphism with age of onset, cognitive function, symptomatology and prognosis in chronic schizophrenia. |
| Abstract | The gene coding for catechol-O-methyltransferase (COMT), which is involved in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia. This study aimed to assess the relationship between a functional polymorphism (Val158Met) of the COMT gene and age of onset (AOO), symptomatology, global cognitive function and prognosis in patients with schizophrenia. The study enrolled 154 patients with schizophrenia from chronic wards. Results failed to show a significant association between the Val158Met polymorphism and the Brief Psychiatric Rating Scale scores, Mini-Mental State Examination scores, and Social and Occupational Functioning Assessment Scale scores, but COMT Val158Met heterozygotes had a later AOO than homozygous patients. However, by further expanding the number of patients to 228 patients, the differences in AOO among the three COMT genotypic groups was not significant. The COMT Val158Met polymorphism did not appear to significantly affect susceptibility, symptomatology, global cognitive function and prognosis in Chinese patients with schizophrenia, but the possible association with AOO merits further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 76 | Pharmacogenetics 2004 May 14: 303-7 |
| PMID | 15115916 |
| Title | Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics. |
| Abstract | In this study we attempted to show that the interaction between NOTCH4 and catechol-O-methyltransferase (COMT) polymorphism predicts the response to typical neuroleptics in schizophrenia. Our sample consisted of 94 Finnish patients with DSM-IV schizophrenia and 98 controls. Several studies have connected COMT and NOTCH4 genes to schizophrenia. We have previously shown that COMT polymorphism is significantly associated with treatment response in schizophrenia. NOTCH4 SNP2 polymorphism has been associated with age of onset in schizophrenia, but there is also a trend that this polymorphism may predict response to typical neuroleptics. In the present sample, there is a strong gene-gene interaction between these genes (P = 0.003) and they have additive effect in treatment response. Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR = 10.25 (95% CI 2.21-47.53), P < 0.001]. This combination of genotypes is also more common in patients considered non-responders than in controls [OR = 3.00 (95% CI 1.33-6.76), P = 0.007]. Our results suggest that an interaction between COMT and NOTCH4 genotypes may predict the treatment response to typical neuroleptics in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 77 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 May 127B: 28-9 |
| PMID | 15108175 |
| Title | COMT158 polymorphism and hostility. |
| Abstract | The main study was designed primarily to compare the clinical effects of four antipsychotics in 157 patients with schizophrenia or schizoaffective disorder. The secondary genetic study, reported here, is based on a subset of 60 patients who consented to genotyping assays. Based on previous work with the catechol-O-methyltransferase (COMT) 158 polymorphism, we hypothesized that the Met-Met homozygotes would be more hostile than the heterozygotes and the Val-Val homozygotes. Hostility ratings at baseline were used to test this hypothesis. The Met-Met homozygotes (N = 7) were found to have significantly higher levels of hostility than the other patients (N = 53). The hypothesis was thus supported. The finding should be replicated in a larger sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 78 | J. Vet. Med. Sci. 2004 Feb 66: 183-7 |
| PMID | 15031547 |
| Title | Breed differences in genotype and allele frequency of catechol O-methyltransferase gene polymorphic regions in dogs. |
| Abstract | Catechol O-methyltransferase (COMT) inactivates catecholamines and catechol-containing drugs such as L-DOPA. The common genetic polymorphism Val158Met in the human COMT gene is suspected to be associated with "persistence" or risk for schizophrenia. In this study, we attempted to identify the canine COMT gene fragment and to find a similar polymorphism and to reveal its genetic distribution among five representative canine breeds. We found that the amplified gene consisted of 663 bp nucleotides and was 84% homologous with the human COMT gene. The single nucleotide polymorphisms, guanine adenine substitution, were observed at the 39th, 216th and 482nd nucleotides. From the genotyping of the 216th polymorphism among 266 dogs by the polymerase chain reaction-restriction fragment length polymorphism method with restriction enzyme EagI, and that of the 482nd polymorphism with restriction enzyme SfcI, we found inter-breed variations of genotypes as well as of allelic frequencies for both of these polymorphic regions. These results suggest that the identified polymorphisms will be useful tools in elucidating the genetic background of canine behavioral traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 79 | Am J Psychiatry 2004 Feb 161: 359-61 |
| PMID | 14754787 |
| Title | Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility. |
| Abstract | The catechol O-methyltransferase (COMT) Val158Met polymorphism has been associated with cognitive and behavioral phenotypes in schizophrenia. Whether COMT genotype is beneficial may depend on phenotype definition. The authors examined the effects of COMT genotype on a task that distinguishes imitation from reversal learning. They hypothesized that the Val and Met alleles would be associated with deficits in imitation learning and reversal learning, respectively. Twenty-six patients with schizophrenia and schizoaffective disorder completed a task requiring alternation between imitation and reversal rules. Met homozygotes showed better acquisition of the imitation rule but greater deficit shifting from imitation to reversal. Val homozygotes had poorer imitation performance and slower reaction times. The Met allele, by increasing tonic dopamine, may promote cognitive stability but limit cognitive flexibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 80 | Mol. Psychiatry 2004 May 9: 510-21 |
| PMID | 14745454 |
| Title | Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders. |
| Abstract | schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 81 | Synapse 2004 Feb 51: 112-8 |
| PMID | 14618678 |
| Title | Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression. |
| Abstract | Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) may both be susceptibility genes for schizophrenia. As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, major depression, and normal controls (n = 15 subjects in each group). We also genotyped two common COMT polymorphisms (-287A/G and 158Val/Met) which might affect its expression. Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients. COMT mRNA levels were unrelated to COMT genotypes. We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral prefrontal cortex. As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 82 | Mol. Psychiatry 2004 May 9: 510-21 |
| PMID | 14745454 |
| Title | Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders. |
| Abstract | schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 83 | Wien. Klin. Wochenschr. 2004 Dec 116: 827-33 |
| PMID | 15690966 |
| Title | [In search of susceptibility genes for schizophrenia]. |
| Abstract | After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 84 | Brain Res. Mol. Brain Res. 2004 Dec 132: 95-104 |
| PMID | 15582150 |
| Title | The molecular genetics of the 22q11-associated schizophrenia. |
| Abstract | schizophrenia has a strong genetic component but the mode of inheritance of the disease is complex and in all likelihood involves interaction among multiple genes and also possibly environmental or stochastic factors. A number of studies have shown that the 22q11 deletion syndrome (22q11DS) is a true genetic subtype of schizophrenia and as such may play an extremely important role in deciphering the genetic basis of schizophrenia. Microdeletions of the 22q11 locus are associated with a staggering increased risk to develop schizophrenia. The same locus has also been implicated by some linkage studies. Systematic examination of individual genes from the 1.5 Mb critical region has identified so far the PRODH and ZDHHC8 as strong candidate schizophrenia susceptibility genes from this locus. Discovery of these genes implicates neuromodulatory aminoacids and protein palmitoylation as important for disease development. Other genes, including the gene encoding for COMT, have been implicated by candidate gene approaches. It therefore appears that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome, where deficiency in more than one gene contributes to the strikingly increased disease risk. Mouse models for individual candidate genes will provide the investigators with the opportunity to start understanding the function of these genes and how they may impact on schizophrenia. Mouse models that carry long-range deletions will likely capture the interactions among the culprit genes and help explain the genetic contribution of this locus to the high risk for schizophrenia. In-depth human and animal model studies of 22q11DS promise to answer critical questions relating to the devastating illness of schizophrenia, whose causes remain largely unknown. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 85 | Psychiatry Res 2004 Nov 129: 29-37 |
| PMID | 15572182 |
| Title | Association of aggressive behavior in Korean male schizophrenic patients with polymorphisms in the serotonin transporter promoter and catecholamine-O-methyltransferase genes. |
| Abstract | The incidence of aggressive behavior in patients with schizophrenia is higher than in the general population. Among particular gene polymorphisms posited to be involved in psychiatric disorders, the catecholamine-O-methyltransferase (COMT) and serotonin transporter (5-HTTPR) genes have been the focus of recent research on aggression. In this study, we hypothesized that both the COMT and the 5-HTTPR genotypes may be dependent on and related to aggression in Korean patients with schizophrenia. The subjects were 168 unrelated male schizophrenic patients diagnosed according to DSM-IV. Among two psychiatric hospital staff and medical university students, 158 unrelated male subjects with no lifetime history of psychiatric disorders were recruited to establish the COMT and 5-HTTPR genotype distribution in the general population. All episodes of aggression from the last discharge to readmission were rated. The Total Overt Aggression Scale (OAS) score (sum of the scores of all episodes of aggression), highest OAS score (highest individual episode score, 0-16), OAS category, and OAS category score (mean score within each category) were recorded. There were statistically significant effects of COMT genotype on the mean OAS 4 (physical aggression against other people) score and the highest OAS score. The most predictive was the OAS 4 score. There was a statistically significant effect of 5-HTTPR genotype on mean total score. Thus, the COMT gene is associated with the severity of aggression and with physical aggression against other people, whereas the 5-HTTPR gene is associated with the summary score of all episodes of aggression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 86 | Brain Res. Mol. Brain Res. 2004 Dec 132: 51-6 |
| PMID | 15548428 |
| Title | Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women. |
| Abstract | schizophrenia is a complex disorder with a polygenic inheritance. Catechol-O-methyltransferase (COMT) plays a significant role in the regulation of dopaminergic systems. A polymorphism at COMT Val108/158Met has been identified in association with schizophrenia. We examined the allele and genotype association of the COMT Val108/158Met polymorphism of 297 unrelated schizophrenic patients who strictly met DSM-IV criteria for schizophrenia, and 341 healthy controls. We found significant difference in allele and genotype frequencies between schizophrenic patients and controls (chi2=13.030; P=0.001). The allele frequency of the COMT-L was 45.79% in the total schizophrenic patients, and 41.50% in controls. The genotype frequency of the COM-LL was 21.2% in the total schizophrenic patients, and 11.4% in controls (OR=2.085; 95% CI=1.350-3.219; chi2=11.293; P=0.001). With a separate sex analysis, the frequency of the COMT-L allele was moderately distributed in male schizophrenia (chi2=6.177; df=2; P=0.046). The COMT-LL genotype had a 1.818-fold increased risk for schizophrenia (OR=1.818; 95% CI=1.010-3.273; chi2=4.048; P=0.044). The frequency of the COMT-L allele was even more significantly distributed in women schizophrenia (chi2=7.797; df=2; P=0.020). The COMT-LL genotype had remarkably more increased risk for schizophrenia (OR=2.456; 95% CI=1.287-4.687; chi2=7.710; P=0.005). In conclusion, our results provide strong evidence for a role of the COMT-L allele and LL genotype in the etiopathophysiology of schizophrenia with a sexual difference. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 87 | Biol. Psychiatry 2004 Nov 56: 677-82 |
| PMID | 15522252 |
| Title | Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. |
| Abstract | The gene encoding catechol-O-methyltransferase (COMT), an enzyme that regulates prefrontal cortex dopamine, contains a common functional polymorphism (val(108/158)met) that influences prefrontal cortex function in an allelic dose-dependent manner. A recent study reported that the COMT val(108/158)met polymorphism influences cognitive- and physiologic-related prefrontal cortex responses to antipsychotic treatment. The present study tested the effects of several COMT polymorphisms on the cognitive response to antipsychotic medication in patients with schizophrenia. Twenty inpatients with schizophrenia or schizoaffective disorder (5 with the val-val genotype, 11 with val-met, and 4 with met-met) were administered cognitive tests at two time points: once after 4 weeks of treatment with antipsychotic medication and once after 4 weeks of placebo administration, according to a counterbalanced, double-blind, within-subject study design. Patients homozygous for the COMT met allele displayed significant improvement on the working memory task after treatment. Patients homozygous for the COMT val allele did not show working memory improvement with treatment. Other COMT polymorphisms were not associated with significant differences between treatment and placebo conditions. These results support other data suggesting that the COMT val(108/158)met polymorphism might be an important factor in the cognitive response to antipsychotic medication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 88 | Am J Psychiatry 2004 Oct 161: 1798-805 |
| PMID | 15465976 |
| Title | Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. |
| Abstract | Deficits in working memory and in prefrontal cortical physiology are important outcome measures in schizophrenia, and both have been associated with dopamine dysregulation and with a functional polymorphism (Val(108/158)Met) in the catechol O-methyltransferase (COMT) gene that affects dopamine inactivation in the prefrontal cortex. The purpose of the present study was to evaluate in patients with schizophrenia the effect of COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug. Thirty patients with acute untreated schizophrenia were clinically evaluated with the Positive and Negative Syndrome Scale, underwent COMT Val/Met genotyping, and entered an 8-week prospective study of olanzapine treatment. Twenty patients completed two 3-T functional magnetic resonance imaging scans at 4 and 8 weeks during performance of N-back working memory tasks. There was a significant interaction of COMT genotype and the effects of olanzapine on prefrontal cortical function. Met allele load predicted improvement in working memory performance and prefrontal physiology after 8 weeks of treatment. A similar effect was found also for negative symptoms assessed with the Positive and Negative Syndrome Scale. These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 89 | Am. J. Hum. Genet. 2004 Nov 75: 807-21 |
| PMID | 15457404 |
| Title | Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. |
| Abstract | Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 90 | Psychiatry Res 2004 Jun 127: 1-7 |
| PMID | 15261699 |
| Title | Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia. |
| Abstract | Several lines of evidence suggest that tardive dyskinesia (TD) may be associated with altered dopaminergic neurotransmission. We hypothesized that deranged dopamine degradation enzyme activities might be related to the susceptibility to TD through altered dopaminergic neurotransmission in the central nervous system. In the present study, we investigated the relationship between the gene polymorphisms of three dopamine degradation enzymes and TD. We genotyped the valine/methionine polymorphism of codon 108/158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the A/G polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia. No significant difference was found in total scores on the Abnormal Involuntary Movement Scale (AIMS) among the subject groups, sorted according to the COMT, MAOA and MAOB genotypes. Moreover, no significant difference was found in allele frequencies between patients with TD and patients without TD for any of the polymorphisms. As both COMT and MAO genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects, but none was observed. Our data, therefore, do not support the hypothesis that polymorphisms in COMT, MAOA, and MAOB genes are involved individually or in combination in the predisposition to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 91 | Malays J Med Sci 2004 Jul 11: 3-11 |
| PMID | 22973121 |
| Title | The genetics of schizophrenia. |
| Abstract | schizophrenia is a complex biological disorder with multifactorial mode of transmission where non-genetic determinants are also play important role. It is now clear that it involves combined effect of many genes, each conferring a small increase in liability to the illness. Thus no causal disease genes or single gene of major effects, only susceptible genes are operating. Given this complexity, it comes as no surprise of the difficulty to find susceptible genes. However, schizophrenia genes have been found at last. Recent studies on molecular genetics of schizophrenia which focused on positional and functional candidate genes postulated to be associated with schizophrenia are beginning to produce findings of great interest. These include neuregulin (NRG-1, 8p12-21), dysbindin, (DTNBP1,6p22.3), G72 (13q34) / D-amino acid oxidase (DAAO,12q24), proline dehydrogenase (PRODH-2, 22q11.21), catechol-O-methyltransferase (COMT, 22q11.21), regulator of G protein signaling (RGS-4), 5HT2A and dopamine D3 receptor (DRD3). Applications of microarrays methods were able to locate positional candidate genes related to dopaminergic, serotonergic and glutamatergic neurotransmission. New genome scan project, seen in the light of previous scans, provide support for schizophrenia candidate region on chromosome 1q, 2q, 5q, 6p, 8p, 10p, 13q,15q and 22q. Other reports described including the application of LD mapping and positional cloning technique, microarray technology and efforts to develop quantitative phenotype. More exciting finding is expected in near future with the completion of Hap Map project. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 92 | J. Neurosci. 2004 Jun 24: 5331-5 |
| PMID | 15190105 |
| Title | Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. |
| Abstract | The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene affects activity of the enzyme and influences performance and efficiency of the prefrontal cortex (PFC); however, although catecholaminergic neurotransmission is implicated, the underlying mechanisms remain elusive because studies of the role of COMT in PFC function are sparse. This study investigated the effect of tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set shifting, which is dependent on catecholamines and the medial PFC (mPFC). Additionally, we investigated the effect of tolcapone on extracellular catecholamines in the mPFC using microdialysis in awake rats. Tolcapone significantly and specifically improved extradimensional (ED) set shifting. Tolcapone did not affect basal extracellular catecholamines, but significantly potentiated the increase in extracellular dopamine (DA) elicited by either local administration of the depolarizing agent potassium chloride or systemic administration of the antipsychotic agent clozapine. Although extracellular norepinephrine (NE) was also elevated by local depolarization and clozapine, the increase was not enhanced by tolcapone. We conclude that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission. These data suggest that the links between COMT activity and PFC function can be modeled in rats and may be specifically mediated by DA. The interaction between clozapine and tolcapone may have implications for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 93 | Neurotox Res 2004 -1 6: 43-50 |
| PMID | 15184104 |
| Title | The genetic relationship of personality to major depression and schizophrenia. |
| Abstract | Since ancient times, dimensions of personality have been linked with the liability to psychiatric illness. In modern times, several research approaches suggest that personality and the liability to psychiatric illness such as schizophrenia and major depression (MD) are influenced by many of the same genes. If this is true, it could shed light on the genetic architecture of psychiatric illness. It could also validate the use of personality measures in unaffected relatives in linkage and association studies of psychiatric illness. This approach could potentially increase statistical power to detect genetic effects. The personality trait neuroticism (N) may be genetically related to MD, while schizotypal traits may be genetically related to schizophrenia. Twin studies have reported that most of the covariation between N and MD is due to shared additive genetic factors. Adoption studies have demonstrated that the biological offspring of schizophrenic mothers are more likely to have schizotypal personality disorder than are children of control mothers. At the current time, only one genome wide scan of N has been published, which does show some overlap in linkage results with genome scans of MD. However, this should be replicated and more rigorously studied. At the present time, there are no established susceptibility genes for MD. When these are established, it will be necessary to assess their relationship with N. Currently, no genome scans of schizotypy have been published. Furthermore, although several putative susceptibility genes for schizophrenia have been reported and replicated, only one--catechol-O-methyltransferase (COMT)--has been tested in schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 94 | Mol. Psychiatry 2004 Oct 9: 962-7 |
| PMID | 15124004 |
| Title | Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. |
| Abstract | The enzyme catechol-o-methyltransferase (COMT) transfers a methyl group from adenosylmethionine to catecholamines including the neurotransmitters dopamine, epinephrine and norepinephrine. This methylation results in the degradation of catecholamines. The involvement of the COMT gene in the metabolic pathway of these neurotransmitters has made it an attractive candidate gene for many psychiatric disorders. In this article, we reported our study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia. Three single nucleotide polymorphisms (SNPs) were genotyped for the 274 such families and within-family transmission disequilibrium tests were performed. SNP rs4680, which is the functional Val/Met polymorphism, showed modest association with the disease by the TRANSMIT, FBAT and PDT programs, while the other two SNPs were negative. These SNPs showed lower level of LDs with each other in the Irish subjects than in Ashkenazi Jews. Haplotype analysis indicated that a haplotype, haplotype A-G-A for SNPs rs737865-rs4680-rs165599, was preferentially transmitted to the affected subjects. This was different from the reported G-G-G haplotype found in Ashkenazi Jews, but both haplotypes shared the Val allele. We concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 95 | Mol. Psychiatry 2004 Sep 9: 859-70 |
| PMID | 15098000 |
| Title | COMT haplotypes suggest P2 promoter region relevance for schizophrenia. |
| Abstract | A recent study found, in a large sample of Ashkenazi Jews, a highly significant association between schizophrenia and a particular haplotype of three polymorphic sites in the catechol-O-methyl transferase, COMT, gene: an IVS 1 SNP (dbSNP rs737865), the exon 4 functional SNP (Val158Met, dbSNP rs165688), and a downstream SNP (dbSNP rs165599). Subsequently, this haplotype was shown to be associated with lower levels of COMT cDNA derived from normal cortical brain tissue, most likely due to cis-acting element(s). As a first step toward evaluating whether this haplotype may be relevant to schizophrenia in populations other than Ashkenazi Jews, we have studied this haplotype in 38 populations representing all major regions of the world. Adding to our previous data on four polymorphic sites in the COMT gene, including the Val158Met polymorphism, we have typed the IVS 1 rs737865 and 3' rs615599 sites and also included a novel IVS 1 indel polymorphism, yielding seven-site haplotype frequencies for normal individuals in the 38 globally distributed populations, including a sample of Ashkenazi Jews. We report that the schizophrenia-associated haplotype is significantly heterogeneous in populations worldwide. The three-site, schizophrenia-associated haplotype frequencies range from 0% in South America to 37.1% in Southwest Asia, despite the fact that schizophrenia occurs at roughly equal frequency around the world. Assuming that the published associations found between the exon 4 Val158Met SNP and schizophrenia are due to linkage disequilibrium, these new haplotype data support the hypothesis of a relevant cis variant linked to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain. The previously described HindIII restriction site polymorphism, located within the P2 promoter, varies within all populations and may provide essential information in future studies of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 96 | Aust N Z J Psychiatry 2004 Apr 38: 254-9 |
| PMID | 15038805 |
| Title | Violence in male patients with schizophrenia: risk markers in a South African population. |
| Abstract | We investigate the role of functional variants in the catecholamine-O-methyl transferase gene (COMT) and the monoamine oxidase-A gene (MOA-A), as well as previously identified non-genetic risk factors in the manifestation of violent behaviour in South African male schizophrenia patients. A cohort of 70 acutely relapsed male schizophrenia patients was stratified into violent and non-violent subsets, based on the presence or absence of previous or current violent behaviour. Standardized violence rating scales were also applied and the COMT/NlaIII and MAO-A promoter region variable number of tandem repeats (VNTR) polymorphisms were genotyped. A multiple logistic regression model based on the clinical, genetic and socio-demographic variables indicated that delusions of control (OR = 3.7, 95% CI = 1.21-11.61) and the combined use of cannabis and alcohol (OR = 6.89, 95% CI = 1.28-37.05) were two significant predictors of violent behaviour in this schizophrenia population. No association was found between the tested polymorphisms and violent behaviour. Although the sample size may have limited power to exclude a minor role for these specific gene variants, such a small contribution would have limited clinical relevance given the strong significance of the non-genetic markers. These findings suggest that currently proactive management of violent behaviour in this schizophrenia population should continue to be based on clinical predictors of violence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 97 | Wien. Klin. Wochenschr. 2004 Dec 116: 827-33 |
| PMID | 15690966 |
| Title | [In search of susceptibility genes for schizophrenia]. |
| Abstract | After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 98 | Psychiatry Res 2004 Nov 129: 29-37 |
| PMID | 15572182 |
| Title | Association of aggressive behavior in Korean male schizophrenic patients with polymorphisms in the serotonin transporter promoter and catecholamine-O-methyltransferase genes. |
| Abstract | The incidence of aggressive behavior in patients with schizophrenia is higher than in the general population. Among particular gene polymorphisms posited to be involved in psychiatric disorders, the catecholamine-O-methyltransferase (COMT) and serotonin transporter (5-HTTPR) genes have been the focus of recent research on aggression. In this study, we hypothesized that both the COMT and the 5-HTTPR genotypes may be dependent on and related to aggression in Korean patients with schizophrenia. The subjects were 168 unrelated male schizophrenic patients diagnosed according to DSM-IV. Among two psychiatric hospital staff and medical university students, 158 unrelated male subjects with no lifetime history of psychiatric disorders were recruited to establish the COMT and 5-HTTPR genotype distribution in the general population. All episodes of aggression from the last discharge to readmission were rated. The Total Overt Aggression Scale (OAS) score (sum of the scores of all episodes of aggression), highest OAS score (highest individual episode score, 0-16), OAS category, and OAS category score (mean score within each category) were recorded. There were statistically significant effects of COMT genotype on the mean OAS 4 (physical aggression against other people) score and the highest OAS score. The most predictive was the OAS 4 score. There was a statistically significant effect of 5-HTTPR genotype on mean total score. Thus, the COMT gene is associated with the severity of aggression and with physical aggression against other people, whereas the 5-HTTPR gene is associated with the summary score of all episodes of aggression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 99 | Brain Res. Mol. Brain Res. 2004 Dec 132: 51-6 |
| PMID | 15548428 |
| Title | Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women. |
| Abstract | schizophrenia is a complex disorder with a polygenic inheritance. Catechol-O-methyltransferase (COMT) plays a significant role in the regulation of dopaminergic systems. A polymorphism at COMT Val108/158Met has been identified in association with schizophrenia. We examined the allele and genotype association of the COMT Val108/158Met polymorphism of 297 unrelated schizophrenic patients who strictly met DSM-IV criteria for schizophrenia, and 341 healthy controls. We found significant difference in allele and genotype frequencies between schizophrenic patients and controls (chi2=13.030; P=0.001). The allele frequency of the COMT-L was 45.79% in the total schizophrenic patients, and 41.50% in controls. The genotype frequency of the COM-LL was 21.2% in the total schizophrenic patients, and 11.4% in controls (OR=2.085; 95% CI=1.350-3.219; chi2=11.293; P=0.001). With a separate sex analysis, the frequency of the COMT-L allele was moderately distributed in male schizophrenia (chi2=6.177; df=2; P=0.046). The COMT-LL genotype had a 1.818-fold increased risk for schizophrenia (OR=1.818; 95% CI=1.010-3.273; chi2=4.048; P=0.044). The frequency of the COMT-L allele was even more significantly distributed in women schizophrenia (chi2=7.797; df=2; P=0.020). The COMT-LL genotype had remarkably more increased risk for schizophrenia (OR=2.456; 95% CI=1.287-4.687; chi2=7.710; P=0.005). In conclusion, our results provide strong evidence for a role of the COMT-L allele and LL genotype in the etiopathophysiology of schizophrenia with a sexual difference. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 100 | Neurotox Res 2004 -1 6: 43-50 |
| PMID | 15184104 |
| Title | The genetic relationship of personality to major depression and schizophrenia. |
| Abstract | Since ancient times, dimensions of personality have been linked with the liability to psychiatric illness. In modern times, several research approaches suggest that personality and the liability to psychiatric illness such as schizophrenia and major depression (MD) are influenced by many of the same genes. If this is true, it could shed light on the genetic architecture of psychiatric illness. It could also validate the use of personality measures in unaffected relatives in linkage and association studies of psychiatric illness. This approach could potentially increase statistical power to detect genetic effects. The personality trait neuroticism (N) may be genetically related to MD, while schizotypal traits may be genetically related to schizophrenia. Twin studies have reported that most of the covariation between N and MD is due to shared additive genetic factors. Adoption studies have demonstrated that the biological offspring of schizophrenic mothers are more likely to have schizotypal personality disorder than are children of control mothers. At the current time, only one genome wide scan of N has been published, which does show some overlap in linkage results with genome scans of MD. However, this should be replicated and more rigorously studied. At the present time, there are no established susceptibility genes for MD. When these are established, it will be necessary to assess their relationship with N. Currently, no genome scans of schizotypy have been published. Furthermore, although several putative susceptibility genes for schizophrenia have been reported and replicated, only one--catechol-O-methyltransferase (COMT)--has been tested in schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 101 | BMC Med. Genet. 2004 Dec 5: 30 |
| PMID | 15613245 |
| Title | Catechol-O-methyltransferase (COMT) Val108/158 Met polymorphism does not modulate executive function in children with ADHD. |
| Abstract | An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children. The Val108/158 Met polymorphism of the COMT gene was genotyped in 118 children with ADHD (DSM-IV). The Wisconsin Card Sorting Test (WCST), Tower of London (TOL), and Self-Ordered Pointing Task (SOPT) were employed to evaluate executive functions. Neuropsychological task performance was compared across genotype groups using analysis of variance. ADHD children with the Val/Val, Val/Met and Met/Met genotypes were similar with regard to demographic and clinical characteristics. No genotype effects were observed for WCST standardized perseverative error scores [F2,97 = 0.67; p > 0.05], TOL standardized scores [F2,99 = 0.97; p > 0.05], and SOPT error scores [F2,108 = 0.62; p > 0.05]. Contrary to the observed association between WCST performance and the Val108/158 Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 102 | Neurotox Res 2004 -1 6: 43-50 |
| PMID | 15184104 |
| Title | The genetic relationship of personality to major depression and schizophrenia. |
| Abstract | Since ancient times, dimensions of personality have been linked with the liability to psychiatric illness. In modern times, several research approaches suggest that personality and the liability to psychiatric illness such as schizophrenia and major depression (MD) are influenced by many of the same genes. If this is true, it could shed light on the genetic architecture of psychiatric illness. It could also validate the use of personality measures in unaffected relatives in linkage and association studies of psychiatric illness. This approach could potentially increase statistical power to detect genetic effects. The personality trait neuroticism (N) may be genetically related to MD, while schizotypal traits may be genetically related to schizophrenia. Twin studies have reported that most of the covariation between N and MD is due to shared additive genetic factors. Adoption studies have demonstrated that the biological offspring of schizophrenic mothers are more likely to have schizotypal personality disorder than are children of control mothers. At the current time, only one genome wide scan of N has been published, which does show some overlap in linkage results with genome scans of MD. However, this should be replicated and more rigorously studied. At the present time, there are no established susceptibility genes for MD. When these are established, it will be necessary to assess their relationship with N. Currently, no genome scans of schizotypy have been published. Furthermore, although several putative susceptibility genes for schizophrenia have been reported and replicated, only one--catechol-O-methyltransferase (COMT)--has been tested in schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 103 | Neurotox Res 2004 -1 6: 43-50 |
| PMID | 15184104 |
| Title | The genetic relationship of personality to major depression and schizophrenia. |
| Abstract | Since ancient times, dimensions of personality have been linked with the liability to psychiatric illness. In modern times, several research approaches suggest that personality and the liability to psychiatric illness such as schizophrenia and major depression (MD) are influenced by many of the same genes. If this is true, it could shed light on the genetic architecture of psychiatric illness. It could also validate the use of personality measures in unaffected relatives in linkage and association studies of psychiatric illness. This approach could potentially increase statistical power to detect genetic effects. The personality trait neuroticism (N) may be genetically related to MD, while schizotypal traits may be genetically related to schizophrenia. Twin studies have reported that most of the covariation between N and MD is due to shared additive genetic factors. Adoption studies have demonstrated that the biological offspring of schizophrenic mothers are more likely to have schizotypal personality disorder than are children of control mothers. At the current time, only one genome wide scan of N has been published, which does show some overlap in linkage results with genome scans of MD. However, this should be replicated and more rigorously studied. At the present time, there are no established susceptibility genes for MD. When these are established, it will be necessary to assess their relationship with N. Currently, no genome scans of schizotypy have been published. Furthermore, although several putative susceptibility genes for schizophrenia have been reported and replicated, only one--catechol-O-methyltransferase (COMT)--has been tested in schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 104 | J Int Neuropsychol Soc 2005 Mar 11: 202-4 |
| PMID | 15962707 |
| Title | The differential clinical and neurocognitive profiles of COMT SNP rs165599 genotypes in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 105 | Sci. China, C, Life Sci. 2005 Jun 48: 263-9 |
| PMID | 16092759 |
| Title | Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method. |
| Abstract | schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world's population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions of COMT and ALDH3B1 genes was detected to be significantly susceptible to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 106 | Br. Med. Bull. 2005 -1 73-74: 107-22 |
| PMID | 16365481 |
| Title | Psychiatric genetics--the new era: genetic research and some clinical implications. |
| Abstract | Impressive advances in the last decade have been made in the genetics and neuroscience of neuropsychiatric illness. Synergies between complex genetics, elaboration of intermediate phenotypes (Egan et al. (2004) schizophrenia. London: Blackwell) and novel applications in neuroimaging (Bookheimer et al. (2000) N Engl J Med, 343, 450-456) are revealing the effects of positively associated disease alleles on aspects of neurological function. Genes such as NRG-1, DISC1, RGS4, COMT, PRODH, DTNBP1, G72, DAAO, GRM3 (Harrison and Weinberger (2005) Mol Psychiatry, 10, 40-68) and others have been implicated in schizophrenia along with 5-HTTPR (Ogilvie et al. (1996) Lancet, 347, 731-733; Caspi et al. (2003) Science, 301, 386-389) and BDNF (Geller et al. (2004) Am J Psychiatry, 161, 1698-1700) in affective disorders. As the genetics and complex neurocircuits of these and disorders are being untangled, parallel applications in pharmacogenomics and gene-based drug metabolism are shaping a drive for personalized medicine. Genetic research and pharmacogenomics suggest that the subcategorization of individuals based on various sets of susceptibility alleles will make the treatment of neuropsychiatric and other illnesses more predictable and effective. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 107 | Eur Arch Psychiatry Clin Neurosci 2005 Jun 255: 159-66 |
| PMID | 15995899 |
| Title | Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? |
| Abstract | schizophrenia and affective disorder have been considered to be nosologically and etiologically distinct disorders. This postulate is challenged by progress in new biological research. Both disorders are strongly influenced by genetic factors; thus genetic research is a main contributor to this discussion. We review current evidence of the genetic relationship between schizophrenia and affective disorders, mainly bipolar disorder (the various genetic research methods have been particularly applied to bipolar disorder). Recent family and twin studies reveal a growing consistency in demonstrating cosegregation between both disorders which is difficult to detect with certainty given the low base rates. Systematic molecular genetic search for specific genes impacting on either disorder has now identified one gene which is apparently involved in both disorders (G72/G30); other candidate genes reveal some evidence to present as susceptibility genes with very modest effects for each of both disorders, although not consistently so (e. g., COMT, BDNF). There is room for speculation about other common susceptibility genes, given the overlap between candidate regions for schizophrenia and those for bipolar disorder emerging from linkage studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 108 | Schizophr. Res. 2005 Feb 73: 27-30 |
| PMID | 15567073 |
| Title | COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case-control study. |
| Abstract | In a multicenter study involving 217 subjects of European ancestry [106 patients with schizophrenia and 111 healthy subjects], we tested the hypothesis that the catechol-O-methyl transferase (COMT) Val(158)Met and/or the brain-derived neurotrophic factor (BDNF) C(270)T gene polymorphisms are associated with schizophrenia. The COMT and BDNF genotype and their allele distribution did not differ between patients with schizophrenia and healthy comparison subjects. These results do not support the hypothesis that the COMT Val(158)Met or BDNF C(270)T gene polymorphisms are associated with liability to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 109 | Nat. Neurosci. 2005 Nov 8: 1586-94 |
| PMID | 16234811 |
| Title | Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. |
| Abstract | Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and COMT genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 110 | Nat. Neurosci. 2005 Nov 8: 1500-2 |
| PMID | 16234808 |
| Title | COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. |
| Abstract | Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMT(L)) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 111 | Nihon Shinkei Seishin Yakurigaku Zasshi 2005 Apr 25: 79-84 |
| PMID | 16220657 |
| Title | [Chromosome 22q11 and schizophrenia]. |
| Abstract | Several human chromosomal regions have been identified as candidate regions that play a role in schizophrenia. Deletion or duplication of chromosome 22q11 is associated with velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), a disorder associated with high rates of schizophrenia as well as physical abnormalities (i.e., cardiovascular, parathyroid, thymic and craniofacial abnormalities). Recent mouse studies have identified several candidate genes for VCFS/DGS within the mouse homologue chromosome 16. Deletion of Tbx1, Prodh and COMT within mouse chromosome 16 causes several physical and behavioral features of VCFS/DGS. As VCFS/DGS is likely to represent a genetic subtype of schizophrenia, pinpointing the genetic basis for this specific subtype will contribute to a better understanding of this neuropsychiatric disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 112 | Am J Psychiatry 2005 Sep 162: 1736-8 |
| PMID | 16135635 |
| Title | No association between schizophrenia and polymorphisms in COMT in two large samples. |
| Abstract | A valine/methionine polymorphism in the catechol O-methyltransferase (COMT) gene has been proposed to influence susceptibility to schizophrenia, as has a COMT haplotype in Ashkenazi Jewish and Irish subjects. The authors examined these hypotheses. They reviewed data from more than 2,800 individuals, including almost 1,200 with schizophrenia, from case-control and family-based European association samples. The authors found no support for the hypothesis that a valine/methionine polymorphism in the COMT gene influences susceptibility to schizophrenia or the hypothesis that a COMT haplotype influences susceptibility to schizophrenia in Ashkenazi Jewish and Irish subjects. The data suggest that the valine allele of COMT does not increase susceptibility to schizophrenia in Europeans and that the Ashkenazi or Irish haplotype does not increase susceptibility. Ethnic variation in the linkage disequilibrium structure at COMT means that the haplotype data may not generalize across populations. However, the authors' examination of the hypothesis that the valine allele confers susceptibility, with a particularly strong effect in Europeans, reveals that no such caveat applies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 113 | Neurosci. Lett. 2005 Nov 389: 21-4 |
| PMID | 16043283 |
| Title | COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study. |
| Abstract | This is the first study of a possible molecular genetic basis for schizophrenia with obsessive-compulsive disorder (OCD). We performed a case-control association study of the catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia-OCD patients, OCD and healthy controls. One hundred and thirteen schizophrenia-OCD patients, 79 OCD patients and 171 control subjects were genotyped for the Val(158)Met polymorphism in the COMT gene. There was no significant difference in allele and genotype distribution of the COMT gene between schizophrenia-OCD patients and healthy controls. The low-activity Met allele and Met/Met genotype were more frequent in OCD men than in schizophrenia-OCD and control individuals. This difference, however, was not statistically significant following correction for multiple comparisons. These results do not support the hypothesis that the COMT Val158Met gene polymorphism is associated with liability to schizophrenia-OCD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 114 | Biol. Psychiatry 2005 Dec 58: 901-7 |
| PMID | 16043133 |
| Title | Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. |
| Abstract | Catechol-O-methyltransferase (COMT) is a strong candidate gene for schizophrenia and cognitive functions disrupted in this disorder. This report examines the relation of COMT genotypes to performance on a battery of working memory tests differing in the cognitive operations to be performed on the material. A large sample of 402 healthy adults were tested on four working memory tests: Spatial Delayed Response (SDR), Word Serial Position Test (WSPT), N-back, and Letter-Number Sequencing. A subsample (n = 246) was tested on the Wisconsin Card Sorting Test (WCST). A saliva swab was used to obtain DNA from all participants. Letter-Number Sequencing, which requires both storage and manipulation of information, was the only working memory test that showed expected differences among COMT genotypes, with the met/met group showing the best performance and the val/val group the poorest performance. As in previous studies, the met/met group also performed better than the val/val group on the WCST. COMT genotypes were not associated with performance on tests measuring simple storage, maintenance of temporal order or updating of information in working memory. Genotype differences in Letter-Number Sequencing and WCST suggest that higher-order components of processing (e.g., mental manipulation) are more closely related to this gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 115 | Neuropsychobiology 2005 -1 52: 83-9 |
| PMID | 16037677 |
| Title | Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment. |
| Abstract | Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 116 | Am. J. Hum. Genet. 2005 Jul 77: 27-40 |
| PMID | 15931594 |
| Title | An entropy-based statistic for genomewide association studies. |
| Abstract | Efficient genotyping methods and the availability of a large collection of single-nucleotide polymorphisms provide valuable tools for genetic studies of human disease. The standard chi2 statistic for case-control studies, which uses a linear function of allele frequencies, has limited power when the number of marker loci is large. We introduce a novel test statistic for genetic association studies that uses Shannon entropy and a nonlinear function of allele frequencies to amplify the differences in allele and haplotype frequencies to maintain statistical power with large numbers of marker loci. We investigate the relationship between the entropy-based test statistic and the standard chi2 statistic and show that, in most cases, the power of the entropy-based statistic is greater than that of the standard chi2 statistic. The distribution of the entropy-based statistic and the type I error rates are validated using simulation studies. Finally, we apply the new entropy-based test statistic to two real data sets, one for the COMT gene and schizophrenia and one for the MMP-2 gene and esophageal carcinoma, to evaluate the performance of the new method for genetic association studies. The results show that the entropy-based statistic obtained smaller P values than did the standard chi2 statistic. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 117 | Biol. Psychiatry 2005 May 57: 1117-27 |
| PMID | 15866551 |
| Title | Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. |
| Abstract | Recent evidence documents that cannabis use by young people is a modest statistical risk factor for psychotic symptoms in adulthood, such as hallucinations and delusions, as well as clinically significant schizophrenia. The vast majority of cannabis users do not develop psychosis, however, prompting us to hypothesize that some people are genetically vulnerable to the deleterious effects of cannabis. In a longitudinal study of a representative birth cohort followed to adulthood, we tested why cannabis use is associated with the emergence of psychosis in a minority of users, but not in others. A functional polymorphism in the catechol-O-methyltransferase (COMT) gene moderated the influence of adolescent cannabis use on developing adult psychosis. Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele. These findings provide evidence of a gene x environment interaction and suggest that a role of some susceptibility genes is to influence vulnerability to environmental pathogens. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 118 | Proc. Natl. Acad. Sci. U.S.A. 2005 Mar 102: 3513-8 |
| PMID | 15716360 |
| Title | Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. |
| Abstract | Dopamine supersensitivity occurs in schizophrenia and other psychoses, and after hippocampal lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts of Dbh (dopamine beta-hydroxylase), Drd4 receptors, Gprk6 (G protein-coupled receptor kinase 6), COMT (catechol-O-methyltransferase), or Th-/-, DbhTh/+ (tyrosine hydroxylase), and in rats born by Cesarean-section. The functional state of D2, or the high-affinity state for dopamine (D2High), was measured in these supersensitive animal brain striata. Increased levels and higher proportions (40-900%) for D2High were found in all these tissues. If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2High states, it suggests that there are many pathways to psychosis, any one of which can be disrupted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 119 | J Neural Transm (Vienna) 2005 Aug 112: 1107-13 |
| PMID | 15583953 |
| Title | Negative association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia. |
| Abstract | Chronic administration of typical antipsychotic agents, which mainly act on the dopamine receptors, implicates a role of dopamine system on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a functional Val158Met polymorphism of Catechol-O-methyltransferase (COMT) gene and TD occurrence and TD severity was investigated in 299 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 166, non-TD: 133). After adjusting the effects of confounding factors, there was no significant association between COMT genotype and TD occurrence (p=0.367). Among TD patients, we found no significant correlation between COMT genotypes and the total scores of abnormal involuntary movement scale (AIMS) (p=0.629). We concluded that this COMT polymorphism might not play a major role in the susceptibility of TD nor on the severity of TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 120 | J Neural Transm (Vienna) 2005 Aug 112: 1107-13 |
| PMID | 15583953 |
| Title | Negative association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia. |
| Abstract | Chronic administration of typical antipsychotic agents, which mainly act on the dopamine receptors, implicates a role of dopamine system on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a functional Val158Met polymorphism of Catechol-O-methyltransferase (COMT) gene and TD occurrence and TD severity was investigated in 299 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 166, non-TD: 133). After adjusting the effects of confounding factors, there was no significant association between COMT genotype and TD occurrence (p=0.367). Among TD patients, we found no significant correlation between COMT genotypes and the total scores of abnormal involuntary movement scale (AIMS) (p=0.629). We concluded that this COMT polymorphism might not play a major role in the susceptibility of TD nor on the severity of TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 121 | Mol. Psychiatry 2005 Apr 10: 353-65 |
| PMID | 15340358 |
| Title | Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val(108/158)Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies. We also find Val(108/158)Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 122 | Bull. Acad. Natl. Med. 2005 May 189: 935-44; discussion 944-7 |
| PMID | 16433464 |
| Title | [Schizophrenic disorders: current etiologic and clinical knowledge]. |
| Abstract | Brain anomalies associated with schizophrenic disorders may be of a cognitive, neurophysiological or neurological nature [the latter being relatively minor and nonspecific]. Brain imaging has revealed early anomalies such as cortical-subcortical atrophy and abnormal gyration. These anomalies can also be present in relatives free of schizophrenic symptoms. This raises the question of what determines the transition from vulnerability to clinical onset. There is now evidence that schizophrenic disorders are true brain diseases. This is based on neuropathological studies, brain imaging and clinical findings such as "soft" neurological signs (pyramidal and extrapyramidal symptoms, coordination difficulties, etc.). Cognitive dysfunctions such as attention and memory disorders and abnormal verbal fluency have also been described. Oculomotor pursuit and auditive evoked potentials have identified specific neurophysiological disorders such as N300 and P50 wave modifications. schizophrenic disorders can also be associated with neuronal abnormalities, notably affecting factors involved in synaptic transmission and plasticity. For example, BDNF protein deficit is linked to certain late-onset forms of schizophrenia. Genetic studies are no longer focusing on a possible disease genotype but rather on phenotypic characteristics determined by simpler genotypes (P50 wave modulation, COMT and BDNF genes). The ultimate objective is to identify high-risk subjects, in order to shorten the treatment delay and thereby improve long-term outcome. The benefit of primary prophylaxis remains to be determined, however. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 123 | Am J Pharmacogenomics 2005 -1 5: 149-60 |
| PMID | 15952869 |
| Title | Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. |
| Abstract | No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 124 | Curr Opin Psychiatry 2005 Mar 18: 135-40 |
| PMID | 16639165 |
| Title | The inheritance of intermediate phenotypes for schizophrenia. |
| Abstract | While schizophrenia is substantially heritable, the mode of inheritance is complex, involving numerous genes of small effect and a non-trivial environmental component. The 'endophenotype' approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly inherited traits. Here we review recent studies applying this method to measures of brain structure, physiology, and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). The results suggest that there are multiple heritable dimensions of central nervous system pathology in schizophrenia, including disturbances in the structure and functioning of frontal lobe systems involved in working memory and executive processes, temporal lobe systems involved in episodic memory, auditory perception, and language processing, and cortical and sub-cortical systems mediating smooth pursuit eye movements and sensorimotor gating. A number of genetic loci that are suspected to play a role in predisposing to schizophrenia, including the DISC1, COMT, neuregulin, dysbindin, and alpha-7 nicotinic receptor genes, appear to affect quantitative variation on one or more of these indicators. Future work is encouraged to address whether each of these neural system dysfunctions are under the influence of a partially distinct set of genes, to elucidate the manner in which multiple genes may coalesce in determining schizophrenia-promoting dysfunction in each neurobehavioral domain, and to clarify the degree of overlap in these quantitative trait loci-endophenotype relationships with other forms of psychosis, particularly bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 125 | J Neuropsychiatry Clin Neurosci 2005 -1 17: 465-71 |
| PMID | 16387984 |
| Title | Association of COMT Val158Met genotype with executive functioning following traumatic brain injury. |
| Abstract | Catechol-O-methyltransferase (COMT) is thought to functionally modulate dopamine neurons, thus likely influencing frontal-executive functioning. High enzyme activity (COMT Val) and low enzyme activity (COMT Met) are functional polymorphisms resulting from a G to A transition in exon 4 (codon 158) of the human COMT gene. Decreased cortical dopamine should result in poorer executive functioning. Therefore, the authors hypothesized that individuals with traumatic brain injury (TBI) and the low enzyme activity polymorphism would perform better on tests of executive functioning than individuals with the high enzyme activity polymorphism. One hundred thirteen individuals referred to the Defense and Veterans Brain Injury Center underwent a comprehensive TBI evaluation and were genotyped for the COMT polymorphism. Comparison of mean differences among the COMT genotype groups for several measures of aspects of executive functioning was conducted using analysis of variance (ANOVA) with adjustment for multiple comparisons. Homozygotes for the higher activity allele made more perseverative responses on the Wisconsin Card Sorting Test, while homozygotes for the lower activity allele had the least number of perseverative responses. While it cannot be determined whether TBI influenced the association of COMT Val158Met to executive functioning, these data extend the known relationship of genotype to executive performance seen in healthy comparison subjects and individuals with schizophrenia to individuals with TBI. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 126 | Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 35-41 |
| PMID | 16281377 |
| Title | [A study of some genes related to serotoninergic and dopaminergic systems and auditory evoked-potentials (P300) in patients with schizophrenia and spectrum disorders and their first-degree relatives]. |
| Abstract | The changes of P300 parameters (lower amplitude and increased latency) are thought to be the most prominent phenomena of schizophrenia. A role of gene polymorphism in P300 generation was supported by several associative studies in psychiatrically well subjects and patients with mental disorders. We studied P300 parameters and the following polymorphisms: T102C for the serotonin receptor type 2A (5-HTR2A) gene, the 5-HTTLPR for the serotonin transporter gene, -809G/A, -616G/C N -52C/T SNPs in the promoter region of the dopamine D4 receptor (DRD4) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) in 74 patients with schizophrenia and spectrum disorders and 71 their first-degree relatives. No association was found between serotonergic system genes and P300. The -809G/A DRD4 gene polymorphism was related to amplitude in all frontal leads (p=0,01) in patients. In relatives, an association was observed between -521C/T DRD4 variants and latency (p=0,005) as well as between the COMT gene polymorphism and P300 amplitude (p=0,004) at the central lead. Thus, the genes involved in dopaminergic system play a role in P300 generation both in patients with schizophrenia and spectrum disorders and their relatives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 127 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S51-9 |
| PMID | 16270245 |
| Title | [Neuroimaging in schizophrenia]. |
| Abstract | This overview is focused on functional neuroimaging including functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). Recent evidence for the "dopamine hypothesis of schizophrenia" is summarized including alterations of presynaptic dopamine metabolism and postsynaptic receptor binding potential. Emphasis is given to dopaminergic challenge studies using amphetamine and AMPT. Several PET and SPECT studies have shown a pronounced increase of amphetamine-induced dopamine release as well as decrease of AMPT-induced dopamine depletion in drug-naive schizophrenic patients, indicating a dysregulation of dopaminergic neurotransmission. Results of studies combining amphetamine challenge and the NMDA receptor antagonist ketamine are related to glutaminergic dysfunction and neurotransmitter interactions. FMRI and PET results demonstrating alterations in task-specific functional connectivity between brain areas are discussed with a focus on the prefrontal cortex and temporal structures. Increase of serotonin-1A receptor binding potential in prefrontal and mesotemporal cortex is related to the serotonin-dopamine interaction. Genetic neuroimaging techniques, including voxel-based morphometry (VBM) and fMRI, revealing significant effects of the dopamine metabolizing enzyme COMT on functional activation in prefrontal areas are also discussed. Functional neuroimaging based on challenge-paradigms in PET as well as task-specific state- or trait-dependent alterations of activation patterns in fMRI, seems to be a promising candidate for the development of biological marker tests for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 128 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50 |
| PMID | 16270244 |
| Title | [Genetic risk factors in schizophrenia]. |
| Abstract | The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 129 | Behav Brain Funct 2005 Oct 1: 19 |
| PMID | 16232322 |
| Title | COMT genetic variation confers risk for psychotic and affective disorders: a case control study. |
| Abstract | Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls. Cases included patients with schizophrenia (n = 196), schizoaffective disorder (n = 62), bipolar disorder (n = 82), major depression (n = 30), and patients diagnosed with either psychotic disorder NOS or depressive disorder NOS (n = 24). SNP rs2097603, the Val/Met variant and SNP rs165599 were significantly associated (p = 0.004; p = 0.05; p = 0.035) with a broad "all affected" diagnosis. Haplotype analysis revealed a potentially protective G-A-A-A haplotype haplotype (-278A/G; rs737865; Val108/158Met; rs165599), which was significantly underrepresented in this group (p = 0.0033) and contained the opposite alleles of the risk haplotype previously described by Shifman et al. Analysis of diagnostic subgroups within the "all affecteds group" showed an association of COMT in patients with psychotic disorders as well as in cases with affective illness although the associated variants differed. The protective haplotype remained significantly underrepresented in most of these subgroups. Our results support the view that COMT variation provides a weak general predisposition to neuropsychiatric disease including psychotic and affective disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 130 | Clin Ther 2005 -1 27 Suppl A: S8-15 |
| PMID | 16198200 |
| Title | Genetic mechanisms of psychosis: in vivo and postmortem genomics. |
| Abstract | The Clinical Brain Disorders Branch Sibling Study data set was initiated in 1996 to examine genetic associations and to identify biological traits associated with susceptibility gene effects. Characterizing genes--and translating their effects on brain development and function--has potential implications for improving the prevention and treatment of schizophrenia. The goal of this article was to discuss the relationship between genetic variation and schizophrenia using in vivo and postmortem genomics. Over the past 2 years, several specific genes have been convincingly associated with schizophrenia risk in a number of populations around the world. Some of the genes that have been studied more extensively include: catechol O-methyltransferase (COMT) (chromosome 22q), dysbindin-1 (chromosome 6p), neuregulin 1 (chromosome 8p), metabotropic glutamate receptor 3 (GRM-3) (chromosome 7q), glutamate decarboxylase 1 (chromosome 2q), and disrupted-in-schizophrenia 1 (DISC1) (chromosome 1q). A functional polymorphism in the COMT gene, which affects prefrontal cortical function by changing dopamine signaling in the prefrontal cortex, has been studied extensively. This gene impacts the regulation of dopamine neuronal activity in the brainstem, which is associated with psychosis. GRM-3 shows similar results on prefrontal function; in postmortem tissue, it has an effect on expression of various glutamate synaptic markers. DISC1 affects hippocampal anatomy and function, whereas dysbindin-1 appears to be a general cognitive capacity gene that is underexpressed in the schizophrenic cortex. Data suggest that these susceptibility genes influence the cortical information processing which characterizes the schizophrenic phenotype. These data add to the evidence that such genes contribute to the pathophysiology of schizophrenia and provide insights into their mechanisms. Thus, genetic variation and its influence on the biological processes underlying schizophrenia may be key to developing future prevention strategies and new treatments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 131 | Psychiatry Res 2005 Sep 136: 83-91 |
| PMID | 16109444 |
| Title | No association found between 158 Val/Met polymorphism of the COMT gene and schizophrenia with minor physical anomalies. |
| Abstract | The catechol-O-methyl transferase (COMT) gene has been a promising candidate in genetic research on schizophrenia because of its function in dopamine metabolism and its location on chromosome 22q11.2, which may be implicated in both schizophrenia and velocardiofacial syndrome (VCFS). To explore the possible genetic contribution of COMT to the development of schizophrenia, we focused on the subgroup of patients with schizophrenia characterized by minor physical anomalies as a phenotype and the 158 Val/Met polymorphism as a genotype. Since some physical anomalies are found in both schizophrenia and VCFS, schizophrenia patients with minor physical anomalies could represent the putative subgroup of schizophrenia linked to a disruption in neurodevelopment. Genotyping for the 158 Val/Met (472 G>A) polymorphism in the COMT gene was done for 239 patients with schizophrenia and 248 normal controls. Our analysis did not yield any significant between-group differences in terms of either allele or genotype frequency. We also could not find any association between the COMT gene and the schizophrenia subgroup with minor physical anomalies, although there was a significant difference in Waldrop total scores between the patients with schizophrenia and the normal controls. Analyses of subgroups based on other clinical variables also did not reveal significant differences. Overall, this study does not support the hypothesis that the 158 Val/Met polymorphism in the COMT gene is associated with schizophrenia in Koreans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 132 | Mol. Psychiatry 2005 Nov 10: 1026-36 |
| PMID | 16027741 |
| Title | Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease. |
| Abstract | Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-->A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-->Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-->A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD+P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD+P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD+P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 133 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Aug 137B: 29-32 |
| PMID | 15965969 |
| Title | Evidence for a common biological basis of the Absorption trait, hallucinogen effects, and positive symptoms: epistasis between 5-HT2a and COMT polymorphisms. |
| Abstract | Absorption represents a disposition to experience altered states of consciousness characterized by intensively focused attention. It is correlated with hypnotic susceptibility and includes phenomena ranging from vivid perceptions and imaginations to mystical experiences. Based on the assumption that drug-induced and naturally occurring mystical experiences share common neural mechanisms, we hypothesized that Absorption is influenced by the T102C polymorphism affecting the 5-HT2a receptor, which is known to be an important target site of hallucinogens like LSD. Based on the pivotal role ascribed to the prefrontal executive control network for absorbed attention and positive symptoms in schizophrenia, it was further hypothesized that Absorption is associated with the VAL158MET polymorphism of the catechol-O-methyltransferase (COMT) gene affecting the dopaminergic neurotransmitter system. The Tellegen Absorption Scale was administered to 336 subjects (95 male, 241 female). Statistical analysis revealed that the group with the T/T genotype of the T102C polymorphism, implying a stronger binding potential of the 5-HT2a receptor, indeed had significantly higher Absorption scores (F = 10.00, P = 0.002), while no main effect was found for the COMT polymorphism. However, the interaction between T102C and COMT genotypes yielded significance (F = 3.89; P = 0.049), underlining the known functional interaction between the 5-HT and the dopaminergic system. These findings point to biological foundations of the personality trait of Absorption. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 134 | Biol. Psychiatry 2005 Jul 58: 23-31 |
| PMID | 15935994 |
| Title | COMT Val108/158 Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome. |
| Abstract | Microdeletions at 22q11.2 greatly increase the risk of schizophrenia in early adulthood (relative risk approximately 25-30). We hypothesized that before the onset of schizophrenia, individuals with 22q11DS would manifest specific cognitive and neurophysiological anomalies (endophenotypes) in common with individuals at high risk for schizophrenia in the general population. We further predicted that the catechol-O-methyltransferase Val(108/158)Met polymorphism, located within the deleted chromosomal segment, would modify the severity of endophenotypic features. 22q11DS adolescents and young adults (aged 13-21) were compared with age- and IQ-matched control subjects on measures that are associated with risk of idiopathic schizophrenia. 22q11DS subjects displayed poorer verbal working memory and expressive language performance than control subjects. Auditory mismatch negativity (MMN) event-related potentials were reduced at frontal electrodes but were intact at temporal sites. Presence of the COMT(108/158)Met allele on the single intact chromosome 22 was associated with more marked MMN amplitude reduction and poorer neuropsychological performance. Neither COMT Val(108/158)Met allele influenced psychiatric symptoms. 22q11DS is associated with neurodevelopmental characteristics that are similar to idiopathic schizophrenia. The COMT Val(108/158)Met polymorphism modifies the severity of endophenotypes for schizophrenia, indicating that impaired catecholamine regulation contributes to neuropsychiatric risk in 22q11DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 135 | Mol. Psychiatry 2005 Aug 10: 765-70 |
| PMID | 15824744 |
| Title | Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. |
| Abstract | There is strong evidence for a genetic contribution to schizophrenia, but the contribution of individual candidate genes remains uncertain. We attempted to replicate a recent meta-analysis that reported an association of the catechol O-methyltransferase (COMT) Val allele with schizophrenia, and suggested that this effect may be moderated by ancestry. We included reports published subsequent to the original meta-analysis, and included a formal test of the moderating effect of ancestry in order to test whether the association operates differently in populations of European ancestry compared to populations of Asian ancestry. A corrected P-value for the 5% significance threshold was employed where appropriate, using Bonferroni's method, and studies that demonstrated departure from Hardy-Weinberg equilibrium among controls were excluded. When all studies were included in a meta-regression, there was evidence for a significant association of COMT Val allele frequency with schizophrenia case status and a significant main effect of ancestry. The interaction of COMT Val allele frequency and ancestry was also significant. However, when only studies that reported allele frequencies that did not depart significantly from Hardy-Weinberg equilibrium among controls were included, these effects were no longer significant. The results of our meta-analysis do not support an association between the COMT Val allele and schizophrenia case status, and do not support recent claims that this association may be moderated by ancestry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 136 | Mol. Psychiatry 2005 Mar 10: 229, 287-98 |
| PMID | 15668720 |
| Title | Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. |
| Abstract | The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V(158)M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [(15)O]H(2)O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 137 | Biol. Psychiatry 2005 Jan 57: 139-44 |
| PMID | 15652872 |
| Title | Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. |
| Abstract | A common functional polymorphism (Val/Met) in the catechol-O-methyltransferase gene (COMT) that markedly affects enzyme activity has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans. It is hypothesized that the high activity Val allele slightly increases risk for schizophrenia through its effect on dopamine-mediated prefrontal information processing. We compared the allele/genotype frequencies of the Val/Met polymorphism in a large independent patient-control sample (862 patient and 928 healthy control subjects) from Han Chinese population, and an update meta-analysis was performed to assess the collective evidence across individual studies. No statistically significant differences were found in allele or genotype frequencies between patient and normal control subjects, although a nonsignificant overrepresentation of the Val allele in schizophrenia patients (odds ratio [OR] = 1.09, 95% confidence interval [CI] = .94-1.26) was suggested. Comparatively, the meta-analysis of all published population-based association studies showed statistically significant evidence for heterogeneity among the group of studies. Stratification of the studies by ethnicity of the samples yielded no significant evidence for an association with the Val allele in Asian population (OR = .96, 95% CI = .85-1.09), nor in European population (OR = 1.06, 95% CI = .95-1.19). Our data provide minimal evidence that the Val allele is a susceptibility factor for schizophrenia in either European or Asian populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 138 | Hum. Genet. 2005 Mar 116: 319-28 |
| PMID | 15645182 |
| Title | Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. |
| Abstract | Catechol-O-methyltransferase (COMT) inactivates circulating catechol hormones, catechol neurotransmitters, and xenobiotic catecholamines by methylating their catechol moieties. The COMT gene has been suggested as a candidate gene for schizophrenia through linkage analyses and molecular studies of velo-cardio-facial syndrome. A coding polymorphism of the COMT gene at codon 108/158 (soluble/membrane-bound form) causing a valine to methionine substitution has been shown to influence enzyme activity, but its association with schizophrenia is inconclusive. We have screened 17 known polymorphisms of the COMT gene in 320 Korean schizophrenic patients and 379 controls to determine whether there is a positive association with a nonsynonymous single-nucleotide polymorphism (rs6267) at codon 22/72 (soluble/membrane-bound form) causing an alanine-to-serine (Ala/Ser) substitution. With the Ala/Ala genotype as a reference group, the combined genotype (Ala/Ser and Ser/Ser)-specific adjusted odds ratio was 1.82 (95% CI = 1.19-2.76; P = 0.005), suggesting the Ser allele as a risk allele for schizophrenia. However, the Val/Met polymorphism was not associated with an increased risk of schizophrenia in Koreans (OR = 0.88, 95% CI = 0.64-1.21; P = 0.43). The Ala72Ser substitution was correlated with reduced COMT enzyme activity. Our results support previous reports that the COMT haplotype implicated in schizophrenia is associated with low COMT expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 139 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Feb 133B: 37-42 |
| PMID | 15635661 |
| Title | Site-specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia. |
| Abstract | The catechol-o-methyltransferase (COMT) gene on chromosome 22q11 has been considered a strong candidate gene for schizophrenia (SZ) susceptibility. A functional Val/Met polymorphism in exon 4, with potential to affect COMT activity has been implicated in SZ, but the results remain inconclusive. We hypothesized that the association of COMT gene with SZ is not strictly a genetic alteration but could involve DNA methylation, as an epigenetic alteration. Thus, we chose to examine the cytosine DNA methylation profile of the human COMT promoter regions, which partially overlaps with the MB-COMT coding region and covers a total of 56 cytosines. Our analysis of 31 brain regions and 51 individual blood samples suggests that the cytosine methylation in his region is restricted to the CpG dinucleotides only. Also, the methylation pattern is nearly identical in the brain and blood with few exceptions. One cytosine (#27) is partially methylated in 5 brain regions and another cytosine (#23) is partially methylated in 81 of 82 samples studied. The exception being the blood DNA from a single SZ patient with prominent extreme negative symptoms, which was completely methylated. Interestingly, there was no difference in methylation at these sites in the blood DNA from three pairs of monozygotic twins discordant for SZ. The results support the use of blood DNA in methylation studies and rule out S-COMT promoter methylation as a common cause of SZ. The unique observation of a completely methylated cytosine 23 in one patient with SZ may have the potential to affect COMT mRNA transcription and gene activity, but remains to be evaluated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 140 | Mol. Psychiatry 2005 Jun 10: 589-97 |
| PMID | 15505638 |
| Title | Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. |
| Abstract | Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 141 | Mol. Psychiatry 2005 Jan 10: 40-68; image 5 |
| PMID | 15263907 |
| Title | Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. |
| Abstract | This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 142 | Bull. Acad. Natl. Med. 2005 May 189: 935-44; discussion 944-7 |
| PMID | 16433464 |
| Title | [Schizophrenic disorders: current etiologic and clinical knowledge]. |
| Abstract | Brain anomalies associated with schizophrenic disorders may be of a cognitive, neurophysiological or neurological nature [the latter being relatively minor and nonspecific]. Brain imaging has revealed early anomalies such as cortical-subcortical atrophy and abnormal gyration. These anomalies can also be present in relatives free of schizophrenic symptoms. This raises the question of what determines the transition from vulnerability to clinical onset. There is now evidence that schizophrenic disorders are true brain diseases. This is based on neuropathological studies, brain imaging and clinical findings such as "soft" neurological signs (pyramidal and extrapyramidal symptoms, coordination difficulties, etc.). Cognitive dysfunctions such as attention and memory disorders and abnormal verbal fluency have also been described. Oculomotor pursuit and auditive evoked potentials have identified specific neurophysiological disorders such as N300 and P50 wave modifications. schizophrenic disorders can also be associated with neuronal abnormalities, notably affecting factors involved in synaptic transmission and plasticity. For example, BDNF protein deficit is linked to certain late-onset forms of schizophrenia. Genetic studies are no longer focusing on a possible disease genotype but rather on phenotypic characteristics determined by simpler genotypes (P50 wave modulation, COMT and BDNF genes). The ultimate objective is to identify high-risk subjects, in order to shorten the treatment delay and thereby improve long-term outcome. The benefit of primary prophylaxis remains to be determined, however. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 143 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S51-9 |
| PMID | 16270245 |
| Title | [Neuroimaging in schizophrenia]. |
| Abstract | This overview is focused on functional neuroimaging including functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). Recent evidence for the "dopamine hypothesis of schizophrenia" is summarized including alterations of presynaptic dopamine metabolism and postsynaptic receptor binding potential. Emphasis is given to dopaminergic challenge studies using amphetamine and AMPT. Several PET and SPECT studies have shown a pronounced increase of amphetamine-induced dopamine release as well as decrease of AMPT-induced dopamine depletion in drug-naive schizophrenic patients, indicating a dysregulation of dopaminergic neurotransmission. Results of studies combining amphetamine challenge and the NMDA receptor antagonist ketamine are related to glutaminergic dysfunction and neurotransmitter interactions. FMRI and PET results demonstrating alterations in task-specific functional connectivity between brain areas are discussed with a focus on the prefrontal cortex and temporal structures. Increase of serotonin-1A receptor binding potential in prefrontal and mesotemporal cortex is related to the serotonin-dopamine interaction. Genetic neuroimaging techniques, including voxel-based morphometry (VBM) and fMRI, revealing significant effects of the dopamine metabolizing enzyme COMT on functional activation in prefrontal areas are also discussed. Functional neuroimaging based on challenge-paradigms in PET as well as task-specific state- or trait-dependent alterations of activation patterns in fMRI, seems to be a promising candidate for the development of biological marker tests for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 144 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50 |
| PMID | 16270244 |
| Title | [Genetic risk factors in schizophrenia]. |
| Abstract | The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 145 | Clin Ther 2005 -1 27 Suppl A: S8-15 |
| PMID | 16198200 |
| Title | Genetic mechanisms of psychosis: in vivo and postmortem genomics. |
| Abstract | The Clinical Brain Disorders Branch Sibling Study data set was initiated in 1996 to examine genetic associations and to identify biological traits associated with susceptibility gene effects. Characterizing genes--and translating their effects on brain development and function--has potential implications for improving the prevention and treatment of schizophrenia. The goal of this article was to discuss the relationship between genetic variation and schizophrenia using in vivo and postmortem genomics. Over the past 2 years, several specific genes have been convincingly associated with schizophrenia risk in a number of populations around the world. Some of the genes that have been studied more extensively include: catechol O-methyltransferase (COMT) (chromosome 22q), dysbindin-1 (chromosome 6p), neuregulin 1 (chromosome 8p), metabotropic glutamate receptor 3 (GRM-3) (chromosome 7q), glutamate decarboxylase 1 (chromosome 2q), and disrupted-in-schizophrenia 1 (DISC1) (chromosome 1q). A functional polymorphism in the COMT gene, which affects prefrontal cortical function by changing dopamine signaling in the prefrontal cortex, has been studied extensively. This gene impacts the regulation of dopamine neuronal activity in the brainstem, which is associated with psychosis. GRM-3 shows similar results on prefrontal function; in postmortem tissue, it has an effect on expression of various glutamate synaptic markers. DISC1 affects hippocampal anatomy and function, whereas dysbindin-1 appears to be a general cognitive capacity gene that is underexpressed in the schizophrenic cortex. Data suggest that these susceptibility genes influence the cortical information processing which characterizes the schizophrenic phenotype. These data add to the evidence that such genes contribute to the pathophysiology of schizophrenia and provide insights into their mechanisms. Thus, genetic variation and its influence on the biological processes underlying schizophrenia may be key to developing future prevention strategies and new treatments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 146 | Hum. Genet. 2005 Mar 116: 319-28 |
| PMID | 15645182 |
| Title | Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. |
| Abstract | Catechol-O-methyltransferase (COMT) inactivates circulating catechol hormones, catechol neurotransmitters, and xenobiotic catecholamines by methylating their catechol moieties. The COMT gene has been suggested as a candidate gene for schizophrenia through linkage analyses and molecular studies of velo-cardio-facial syndrome. A coding polymorphism of the COMT gene at codon 108/158 (soluble/membrane-bound form) causing a valine to methionine substitution has been shown to influence enzyme activity, but its association with schizophrenia is inconclusive. We have screened 17 known polymorphisms of the COMT gene in 320 Korean schizophrenic patients and 379 controls to determine whether there is a positive association with a nonsynonymous single-nucleotide polymorphism (rs6267) at codon 22/72 (soluble/membrane-bound form) causing an alanine-to-serine (Ala/Ser) substitution. With the Ala/Ala genotype as a reference group, the combined genotype (Ala/Ser and Ser/Ser)-specific adjusted odds ratio was 1.82 (95% CI = 1.19-2.76; P = 0.005), suggesting the Ser allele as a risk allele for schizophrenia. However, the Val/Met polymorphism was not associated with an increased risk of schizophrenia in Koreans (OR = 0.88, 95% CI = 0.64-1.21; P = 0.43). The Ala72Ser substitution was correlated with reduced COMT enzyme activity. Our results support previous reports that the COMT haplotype implicated in schizophrenia is associated with low COMT expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 147 | Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50 |
| PMID | 16270244 |
| Title | [Genetic risk factors in schizophrenia]. |
| Abstract | The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 148 | Biol. Psychiatry 2006 Sep 60: 663-4; author reply 664-5 |
| PMID | 16899231 |
| Title | COMT Association Data in Schizophrenia: New Caveats. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 149 | Mol. Psychiatry 2006 Feb 11: 116-7 |
| PMID | 16247488 |
| Title | A novel protein isoform of catechol O-methyltransferase (COMT): brain expression analysis in schizophrenia and bipolar disorder and effect of Val158Met genotype. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 150 | Eur. J. Hum. Genet. 2006 Jun 14: 669-80 |
| PMID | 16721403 |
| Title | Molecular genetic studies of schizophrenia. |
| Abstract | The study of schizophrenia genetics has confirmed the importance of genes in etiology, but has not so far identified the relationship between observed genetic risks and specific DNA variants, protein alterations or biological processes. In spite of many limitations, numerous regions of the human genome give consistent, although by no means unanimous, support for linkage, which is unlikely to occur by chance. Two recent shifts have been evident in the field. First, a series of studies combining linkage and association analyses in the same family sets have identified promising candidate genes (DTNBP1, NRG1, G72/G30, TRAR4). Although a consensus definition of replication for genetic association in a complex trait remains difficult to achieve, the evidence for two of these (dystrobrevin binding protein 1 (DTNBP1), NRG1) is strong. Second, a series of studies combining association with functional investigation of changes in the associated gene in schizophrenia have also identified several candidate genes (COMT, RGS4, PPP3CC, ZDHHC8, AKT1). Somewhat surprisingly, the loci implicated by these studies have proven less robust in replication, although the number of replication studies remains small in several cases. Assessment of the combined evidence for the DTNBP1 gene gives some insight into the nature of the problems remaining to be solved. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 151 | Psychiatry Res 2006 Jun 143: 13-9 |
| PMID | 16712949 |
| Title | Performance on the Wisconsin Card Sorting Test in schizophrenia and genes of dopaminergic inactivation (COMT, DAT, NET). |
| Abstract | The aim of the study was to test an association between polymorphisms of genes connected with dopaminergic inactivation in prefrontal cortex [catechol-O-methyltransferase (COMT), dopamine transporter (DAT), norepinephrine transporter (NET)], and performance on the Wisconsin Card Sorting Test (WCST), in schizophrenic patients. The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured. Genotyping was done for the Val108(158)Met polymorphism of the COMT gene (79 patients), the 3'UTR VNTR polymorphism of the DAT gene (124 patients) and the 1287 A/G polymorphism of the NET gene (63 patients). Male schizophrenic patients with Val/Val genotype of COMT obtained better results on WCST-P, while female patients had worse results on the WCST-NP compared with the remaining genotypes. There was a slight trend for patients with the A9/A9 genotype of DAT and with the A/A genotype of NET to perform better on some domains of the WCST, compared with other genotypes. A limitation to the interpretation of results could be small number of patients studied as well as variable psychopathological state and medication during cognitive testing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 152 | Psychiatr Hung 2006 -1 21: 404-12 |
| PMID | 17438657 |
| Title | [Gene polymorphism and gene expression in schizophrenia]. |
| Abstract | The author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 153 | Psychiatry Clin. Neurosci. 2006 Dec 60: 764-7 |
| PMID | 17109713 |
| Title | Schizotypy, attention deficit hyperactivity disorder, and dopamine genes. |
| Abstract | Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 154 | Psychiatr. Genet. 2006 Dec 16: 229-30 |
| PMID | 17106420 |
| Title | Bipolar 1 disorder is not associated with the RGS4, PRODH, COMT and GRK3 genes. |
| Abstract | Although current psychiatric nosology separates bipolar disorder and schizophrenia into non-overlapping categories, there is growing evidence of a partial aetiological overlap between them from linkage, genetic epidemiology and molecular genetics studies. Thus, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. In this study we investigated a total of 15 single nucleotide polymorphisms (SNPs), and all possible haplotypes, of genes that have been previously implicated in schizophrenia or bipolar disorder - RGS4, PRODH, COMT and GRK3 - in a sample of 213 cases with bipolar affective disorder type 1 and 197 controls from Scotland. We analysed the polymorphisms allele-wise, genotype-wise and, for each gene, haplotype-wise but obtained no result that reached nominal significance (p<0.05) for an association with the disease status. In conclusion, we could not find evidence of association between RGS4, PRODH, COMT and GRK3 genes and bipolar affective disorder 1 in the Scottish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 155 | Neuron 2006 Oct 52: 139-53 |
| PMID | 17015232 |
| Title | Neurobiology of schizophrenia. |
| Abstract | With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 156 | CNS Spectr 2006 Oct 11: 745-8 |
| PMID | 17008817 |
| Title | Warriors versus worriers: the role of COMT gene variants. |
| Abstract | Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 157 | J Clin Psychiatry 2006 -1 67 Suppl 10: 5-12 |
| PMID | 16965190 |
| Title | A review of agitation in mental illness: burden of illness and underlying pathology. |
| Abstract | Agitation has been poorly addressed as a unique entity in many psychiatric disorders. Recent medical literature and a range of instruments have measured agitation in various clinical settings. Agitation is a common problem in many patients with schizophrenia, bipolar mania, or dementia. Moreover, agitation adversely impacts many facets of the healing process, including direct patient care, caregiver burden, and community resources. Frontal lobe dysfunction and mutations in the catechol O-methyltransferase (COMT) gene involved in dopamine metabolism and catecholamine inactivation have been linked to agitation in patients with schizophrenia and bipolar disorder. Cerebral impairment and deficits in cognitive function predispose patients with dementia to agitation. In patients with Alzheimer's dementia, both frontal and temporal lobe pathology may be associated with agitation. Addressing agitation as a symptom of psychiatric illness would represent a great opportunity for therapeutic intervention and the alleviation of patient suffering, family burden, and societal costs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 158 | Psychiatry Res 2006 Oct 147: 221-6 |
| PMID | 16952445 |
| Title | Prefrontal dysfunction in schizophrenia controlling for COMT Val158Met genotype and working memory performance. |
| Abstract | Earlier studies with functional imaging in schizophrenia have demonstrated dysfunction of the dorsolateral prefrontal cortex during working memory. Controlling for behavioral performance and for catechol-O-methyltransferase (COMT) Val158Met genotype, we here demonstrate in a functional magnetic resonance imaging paradigm that patients recruit greater neuronal resources in prefrontal cortex during working memory, suggesting that this phenotype is a core functional trait of the disease. We also replicated earlier findings that the Val allele of the COMT polymorphism is associated with greater engagement of the prefrontal cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 159 | Schizophr. Res. 2006 Oct 87: 21-7 |
| PMID | 16860541 |
| Title | Analysis of ProDH, COMT and ZDHHC8 risk variants does not support individual or interactive effects on schizophrenia susceptibility. |
| Abstract | Synergistic interaction between genes on chromosome 22q11 recently has been proposed as a possible mechanism which could confer increased risk for schizophrenia. Based on this hypothesis, our study aimed to explore main, cis- and trans-interacting effects of three candidate genes on 22q11, ProDH, COMT and ZDHHC8. We selected four putative risk variants, residing within these genes, ProDH 1945, ProDH 2026, COMT ValMet and ZDHHC8 rs175174, and studied these in a large family-based schizophrenia association sample of European origin (488 Bulgarian parent-offspring trios). The presence of interaction between the variants was tested by conditional logistic regression analysis based on a case-pseudocontrol design. Our study did not find statistical evidence for allelic (investigation of ProDH markers only), genotypic, haplotypic, or interactive effects between ProDH, COMT and ZDHHC8. Our data do not support the hypothesis that an interaction between these genes influences susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 160 | Schizophr. Res. 2006 Oct 87: 28-31 |
| PMID | 16828262 |
| Title | COMT genotype and manic symptoms in schizophrenia. |
| Abstract | Inconsistencies in the relation between COMT variation and schizophrenia may be clarified by careful delineation of a target phenotype. The present study reports a significant association between a COMT haplotype and the severity of manic symptoms in 162 patients with schizophrenia or schizoaffective disorder (SZ). These data suggest that the effect of COMT variation may be associated with comorbid manic symptoms in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 161 | Eur. Psychiatry 2006 Jul 21: 338-42 |
| PMID | 16815691 |
| Title | Associations between COMTVal158Met polymorphism and cognition: direct or indirect effects? |
| Abstract | Previous work suggests that reaction time variability (RTV) in attentional tasks, as a measure of cognitive stability, is associated with degree of Val loading in COMT Val(158)Met genotype, and that this association may be relevant for the aetiology of schizophrenia. This study examined (i) to what degree RTV pertaining to tasks of varying cognitive complexity would be associated with increased risk for schizophrenia and (ii) to what degree this would be mediated by Val loading. COMT genotyping was investigated in a sample of 23 patients with schizophrenia, 33 first-degree relatives, and 21 controls. All participants performed the Flanker continuous performance test. schizophrenia liability was associated with number of correct trials of the Flanker test, but not with RTV, and this association was not mediated by COMT Val(158)Met genotype. Similarly, Met loading was associated with number of correct trials and with RTV, but this was not mediated by schizophrenia liability. Associations between COMT Val(158)Met genotype and RTV do not appear to reflect transmission of schizophrenia liability in families. Differential associations with Val and Met alleles across studies suggest indirect effects through gene-gene interactions or the influence of a functional polymorphism near COMT Val(158)Met. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 162 | Mol. Psychiatry 2006 Sep 11: 867-77, 797 |
| PMID | 16786032 |
| Title | Impact of complex genetic variation in COMT on human brain function. |
| Abstract | Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a working-memory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3' region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 163 | Brain Res. 2006 Jun 1097: 26-30 |
| PMID | 16725119 |
| Title | Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia. |
| Abstract | A large body of evidence suggests that suicidal behavior is associated with altered noradrenergic neurotransmission. Norepinephrine is degraded by monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT). Our hypothesis is that the genes encoding MAOA and COMT might contain genetic variants conferring increased risk for suicidal behavior in schizophrenia and that both genes may interact each other. In order to test this hypothesis, we genotyped the promoter VNTR polymorphism in the MAOA gene and three COMT polymorphisms: -287A>G, Val/Met and 3'UTR C Ins/Del in a cohort of 270 schizophrenics in which 92 attempted suicide. No association between suicide attempt and the MAOA VNTR (P = 0.382), Val108/158Met (P = 0.788) or -287A>G (P = 0.420) polymorphisms was found, however, a slight significant finding was found for 3'UTR polymorphism (P = 0.050). Haplotype analysis for COMT gene revealed no association between suicide attempts and haplotype distribution (P = 0.451). As we tested for epistasis between MAOA VNTR and COMT Val/Met, we found no significant interaction in conferring risk for suicide attempts (P = 0.545). These results suggest that epistasis between MAOA and COMT genes may not influence suicidal behavior in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 164 | Yi Chuan 2006 Apr 28: 403-6 |
| PMID | 16606590 |
| Title | [An association study between paranoid schizophrenia and four genes involved in dopamine metabolism]. |
| Abstract | schizophrenia is a complex disease caused by interactions among multiple genes. Reports of one of its susceptibility genes, ethyltracatechol-O-mnsferase (COMT) have been conflicting. In the present study on paranoid schizophrenia, we have performed a multilocus association study to analyze the interactions among 4 genes that are involved in dopamine metabolism. Result supports the hypothesis that COMT-136-BclI regulates Val108/158Met. When the genotype of the former is CC, Met (A) is the genotype of susceptibility allele Val108/158Met; and when the genotype of the former is GG, Val (G) is the genotype of susceptibility allele Val108/158Met. This new hypothesis may explain the conflicting results about Val108/158Met (COMT) obtained by single-locus analyses. It also illustrates that multilocus analysis is necessary for the research of complex diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 165 | Clin. Genet. 2006 Mar 69: 234-8 |
| PMID | 16542388 |
| Title | Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome. |
| Abstract | Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O-methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val(158)Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val(158)Met genotype impacts upon cognition in children with 22q11DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 166 | Biol. Psychiatry 2006 Jul 60: 141-51 |
| PMID | 16476412 |
| Title | Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. |
| Abstract | This review summarizes our current understanding of catechol-o-methyltransferase (COMT) and how it relates to brain function and schizophrenia. We begin by considering the COMT gene, its transcripts and proteins, and its relevance for central catecholamine function. We then describe how variation in COMT activity affects the function of the prefrontal cortex (PFC) and associated areas, reviewing evidence that COMT modulates executive function and working memory and highlighting recent data that also implicate it in emotional processing. Finally, we discuss briefly the genetic association between COMT and schizophrenia, focusing in particular on the complex interaction of functional loci within the gene that may underlie the mixed results of studies to date. We conclude by outlining preliminary data indicating that COMT is a promising therapeutic target for ameliorating the cognitive deficits associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 167 | Eur. Psychiatry 2006 Jan 21: 70-3 |
| PMID | 16414251 |
| Title | Is there an association between the COMT gene and P300 endophenotypes? |
| Abstract | P300 wave anomalies correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The COMT gene is thought to influence cognitive performance and to be a susceptibility gene for schizophrenia. Unlike two previous studies, we found no significant influence of the COMT gene on P300 amplitude or latency in 189 individuals examined. The well-supported role of the COMT gene both in dopamine catabolism as well as in prefrontal cognition makes a strong theoretical case for the influence of COMT Val158Met polymorphism on P300 endophenotypes. However, the available neurophysiologic evidence suggests that any such association, if present, must be very subtle. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 168 | Neuroreport 2006 Jan 17: 95-9 |
| PMID | 16361958 |
| Title | Effects of catechol-O-methyltransferase Val158Met polymorphism on the cognitive stability and aggression in the first-onset schizophrenic patients. |
| Abstract | We assessed catechol-O-methyltransferase (COMT) polymorphism in 132 first-onset schizophrenic patients and 80 healthy controls. The relationship between COMT polymorphism and cognitive function, aggression and psychiatric symptoms was tested in the schizophrenic group. COMTL carrier had higher digit span score and lower similarity score than COMTH homozygote. COMTL carrier had higher attention and delusion scores and lower inappropriate affect scores than COMTH homozygote. Attention and delusion scores of COMTL allele were higher than COMTH allele. COMTL group had higher aggression than COMTH homozygote. Our results support the theory that COMTL allele was related with increased tonic dopamine activity and cognitive 'stability', which may induce cognitive inflexibility in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 169 | Psychiatry Res 2006 Jun 143: 13-9 |
| PMID | 16712949 |
| Title | Performance on the Wisconsin Card Sorting Test in schizophrenia and genes of dopaminergic inactivation (COMT, DAT, NET). |
| Abstract | The aim of the study was to test an association between polymorphisms of genes connected with dopaminergic inactivation in prefrontal cortex [catechol-O-methyltransferase (COMT), dopamine transporter (DAT), norepinephrine transporter (NET)], and performance on the Wisconsin Card Sorting Test (WCST), in schizophrenic patients. The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured. Genotyping was done for the Val108(158)Met polymorphism of the COMT gene (79 patients), the 3'UTR VNTR polymorphism of the DAT gene (124 patients) and the 1287 A/G polymorphism of the NET gene (63 patients). Male schizophrenic patients with Val/Val genotype of COMT obtained better results on WCST-P, while female patients had worse results on the WCST-NP compared with the remaining genotypes. There was a slight trend for patients with the A9/A9 genotype of DAT and with the A/A genotype of NET to perform better on some domains of the WCST, compared with other genotypes. A limitation to the interpretation of results could be small number of patients studied as well as variable psychopathological state and medication during cognitive testing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 170 | Brain Res. 2006 Jun 1097: 26-30 |
| PMID | 16725119 |
| Title | Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia. |
| Abstract | A large body of evidence suggests that suicidal behavior is associated with altered noradrenergic neurotransmission. Norepinephrine is degraded by monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT). Our hypothesis is that the genes encoding MAOA and COMT might contain genetic variants conferring increased risk for suicidal behavior in schizophrenia and that both genes may interact each other. In order to test this hypothesis, we genotyped the promoter VNTR polymorphism in the MAOA gene and three COMT polymorphisms: -287A>G, Val/Met and 3'UTR C Ins/Del in a cohort of 270 schizophrenics in which 92 attempted suicide. No association between suicide attempt and the MAOA VNTR (P = 0.382), Val108/158Met (P = 0.788) or -287A>G (P = 0.420) polymorphisms was found, however, a slight significant finding was found for 3'UTR polymorphism (P = 0.050). Haplotype analysis for COMT gene revealed no association between suicide attempts and haplotype distribution (P = 0.451). As we tested for epistasis between MAOA VNTR and COMT Val/Met, we found no significant interaction in conferring risk for suicide attempts (P = 0.545). These results suggest that epistasis between MAOA and COMT genes may not influence suicidal behavior in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 171 | Neuroreport 2006 Jan 17: 95-9 |
| PMID | 16361958 |
| Title | Effects of catechol-O-methyltransferase Val158Met polymorphism on the cognitive stability and aggression in the first-onset schizophrenic patients. |
| Abstract | We assessed catechol-O-methyltransferase (COMT) polymorphism in 132 first-onset schizophrenic patients and 80 healthy controls. The relationship between COMT polymorphism and cognitive function, aggression and psychiatric symptoms was tested in the schizophrenic group. COMTL carrier had higher digit span score and lower similarity score than COMTH homozygote. COMTL carrier had higher attention and delusion scores and lower inappropriate affect scores than COMTH homozygote. Attention and delusion scores of COMTL allele were higher than COMTH allele. COMTL group had higher aggression than COMTH homozygote. Our results support the theory that COMTL allele was related with increased tonic dopamine activity and cognitive 'stability', which may induce cognitive inflexibility in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 172 | Psychiatry Clin. Neurosci. 2006 Dec 60: 764-7 |
| PMID | 17109713 |
| Title | Schizotypy, attention deficit hyperactivity disorder, and dopamine genes. |
| Abstract | Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 173 | Psychiatry Clin. Neurosci. 2006 Dec 60: 764-7 |
| PMID | 17109713 |
| Title | Schizotypy, attention deficit hyperactivity disorder, and dopamine genes. |
| Abstract | Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 174 | Behav Brain Funct 2006 -1 2: 42 |
| PMID | 17173666 |
| Title | Lack of association between COMT gene and deficit/nondeficit schizophrenia. |
| Abstract | The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states. schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients. Eighty-six schizophrenia cases that met DSM-IV criteria for schizophrenia were recruited. Additional categorization into deficit and nondeficit syndrome was performed using the Schedule for the Deficit Syndrome (SDS). A healthy comparison group (n = 50) matched to cases on age and ethnicity was recruited. Allele and genotype frequencies of the Val158Met polymorphism were compared among healthy controls, and schizophrenia cases with the deficit (n = 21), and nondeficit syndrome (n = 65). There was a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls (p = 0.004). No significant differences in allele or genotype frequencies were observed between deficit and nondeficit cases. Results from this preliminary analysis failed to show an effect of COMT gene on deficit schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 175 | World J. Biol. Psychiatry 2006 -1 7: 238-45 |
| PMID | 17071544 |
| Title | Association study of COMT gene Val158Met polymorphism with auditory P300 and performance on neurocognitive tests in patients with schizophrenia and their relatives. |
| Abstract | A number of studies have reported an association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and neuropsychological traits in patients with schizophrenia, their relatives and healthy controls, with the Met allele carriers performing better on neurocognitive tasks than those with the Val allele. But the association was not confirmed in all studies. The present paper was aimed at further investigation of the COMT gene relationship with some neurocognitive traits, assessing mainly working and verbal memory, and to P300 event-related potentials (auditory oddball). A total sample of 319 individuals, including schizophrenic patients, their relatives and controls, was studied. No significant differences in performance of neurocognitive tasks were found by Val158Met genotypes. An association was observed between the Met/Met genotype and higher amplitude in centro-parietal area in relatives. Factors that could explain the non-replication of previous studies on the COMT gene polymorphism and neurocognitive traits are discussed. We suggest here that (1) Val158Met polymorphism rather exerts a modifying influence on brain activation in general than impacts directly on performance of the particular neurocognitive test, and (2) P300 amplitude seems to be a correlate of this activation reflecting, along with information processing, the subject's affective and personality features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 176 | Schizophr. Res. 2006 Dec 88: 251-9 |
| PMID | 17008057 |
| Title | Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome. |
| Abstract | Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 177 | Hum. Mol. Genet. 2006 Nov 15: 3132-45 |
| PMID | 16984965 |
| Title | Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. |
| Abstract | The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P=0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P=0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P=0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 178 | Zh Nevrol Psikhiatr Im S S Korsakova 2006 -1 106: 57-63 |
| PMID | 16921721 |
| Title | [Dopamine system genes interaction and neurocognitive traits in patients with schizophrenia, their relatives and healthy controls from general population]. |
| Abstract | To elucidate main effects of dopamine receptor D4 (DRD4) and cathecol-O-methyltransferase (COMT) genes as well as their interaction effect on neurocognitive traits, DRD4 gene polymorphisms (-809G/A, -521C/T) and the COMT gene Val158Met polymorphism, along with characteristics of verbal memory, executive functions and peculiarities of associative processes, have been studied in 150 patients with schizophrenia, 83 their relatives and 118 mentally healthy subjects without positive family history of psychosis. A main effect of -521C/T polymorphism and DRD4 (-521C/T).Vall58Met polymorphisms interaction were found for verbal fluency, carriers of the Val/Val+CC and the Met/Met+TT genotypes performing better on this task as compared to other genotypes. An interaction DRD4 (-521C/T).Val158Met effect on originality of speech associations was observed in the combined group of unaffected individuals (relatives and controls), with lower scores of the trait in those with the Met/Met+CC genotype. The COMT-DRD4 (-809G/A) interaction effect on working memory was demonstrated for patients and unaffected individuals, homozygotes for the Val and the G alleles having the best results and homozygotes for the Met and the A alleles--the worst ones. The data obtained suggest the relationship of DRD4 and COMT genes with different characteristics of executive functions but not with verbal memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 179 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Dec 141B: 935-8 |
| PMID | 16921496 |
| Title | Catechol-O-methyltransferase and the clinical features of psychosis. |
| Abstract | A functional polymorphism (Val-158-Met) at the Catechol-O-methyltransferase (COMT) locus has been identified as a potential etiological factor in schizophrenia. Yet the association has not been convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To clarify the putative association, we performed an exploratory analysis to test for association between COMT and five psychosis symptom scales. These were derived through factor analysis of the Operational Criteria Checklist for Psychiatric Illness. Our sample was the Irish Study of High Density schizophrenia Families, a large collection consisting of 268 multiplex families. This sample has previously shown a small but significant effect of the COMT Val allele in conferring risk for schizophrenia. We tested for preferential transmission of COMT alleles from parent to affected offspring (n = 749) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression). Significant overtransmission of the Val allele was found for mania (P < 0.05) and depression (P = 0.01) scales. Examination of odds ratios (ORs) revealed a heterogeneous effect of COMT, whereby it had no effect on Negative Symptoms, but largest impact on Depression (OR = 1.4). These results suggest a modest affective vulnerability conferred by this allele in psychosis, but will require replication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 180 | Hum. Mol. Genet. 2006 Sep 15: 2804-12 |
| PMID | 16905560 |
| Title | RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. |
| Abstract | Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 181 | Schizophr. Res. 2006 Sep 86: 1-14 |
| PMID | 16842972 |
| Title | Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. |
| Abstract | Over 130 genes have been associated with schizophrenia in genetic studies. None of these has reached a sufficient level of confidence to be accepted as a universal susceptibility gene and problems of replicability suggest that many may be false positives. Nevertheless, these genes can be grouped into distinct families related to glutamate transmission (in particular related to NMDA receptor function), the control of synaptic plasticity, dopaminergic transmission, oxidative stress, glutathione and quinone metabolism and oligodendrocyte viability. These families mirror the processes disrupted in the schizophrenic brain and certain gene families can be linked together to form a clearly defined signalling cascade involved in the phenomenon of NMDA receptor-dependent long-term potentiation and synaptic plasticity, that may be interconnected with oligodendrocyte and oxidative stress-related pathways. Many of the protein products of these genes interact with each other, forming complex integrated networks. Certain high-interest genes (for example DISC1, NRG1, COMT) may exert multiple effects on different areas of these pathways, while others exert more specific effects on certain branches. The convergence of a large number of genes on a definable signaling network raises the possibility of numerous interactions between gene candidates, and suggests that a targeted multigenic pathway approach would be useful in gene association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 182 | Hum. Genet. 2006 Sep 120: 160-70 |
| PMID | 16783572 |
| Title | A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia. |
| Abstract | Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 183 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jul 141B: 504-12 |
| PMID | 16741933 |
| Title | Lack of influence of COMT and NET genes variants on executive functions in schizophrenic and bipolar patients, their first-degree relatives and controls. |
| Abstract | Abnormal dopaminergic function in the prefrontal cortex (PFC) may be a key factor in the etiopathogeny of schizophrenia and bipolar disorder. Both schizophrenic and bipolar subjects have executive functions (EF) deficits, thought to reflect abnormal PFC function. The main inactivation pathways for dopamine in the PFC are enzymatic cleavage by the Carboxy-O-Methyl-Transferase (COMT) and reuptake by the nor-epinephrine transporter (NET). Our aim in this study was to replicate previous studies that investigated influence of the COMT genotype on EF in schizophrenic subjects, their relatives and controls and extend their scope by including bipolar patients, and their relatives and by exploring NET gene polymorphisms influence on executive performances. We investigated one functional polymorphism of the COMT gene and two polymorphisms of the NET gene. EF were assessed by means of the Trail Making Test (TMT) and the Wisconsin Card Sorting Test (WCST). We assessed the effect of each of the three genotypes on EF for the whole sample (N = 318) and separately in schizophrenic (N = 66), bipolar (N = 94) and healthy subjects (i.e., relatives and controls N = 158). Separate analyses were performed because of the presence, in patients samples, of potentially confounding factors, especially medication. Genotype had no significant effect on the cognitive measures in any of the analyses (for the two EF measures, the three polymorphisms, and the four groups). In our sample we found no evidence in favor of a major effect of COMT or NET polymorphisms on the two tests of EF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 184 | Biol. Psychiatry 2006 Sep 60: 578-84 |
| PMID | 16730334 |
| Title | Prefrontal electrophysiologic "noise" and catechol-O-methyltransferase genotype in schizophrenia. |
| Abstract | Increased variability of stimulus-induced prefrontal electromagnetic activity ("noise") has been associated with genetic risk for schizophrenia. On the basis of animal experiments and computational models, we have predicted that this prefrontal "noise" phenotype would be related to variation in prefrontal dopamine (DA) signaling, which itself might be abnormal in schizophrenia. In the present study, the effect of a functional single nucleotide polymorphism (val(108/158)met) within the catechol-O-methyltransferase (COMT) gene on prefrontal "noise" was examined, because the COMT enzyme is involved in cortical synaptic dopamine metabolism and weakly predictive of risk for schizophrenia. A Caucasian sample comprising 112 unrelated normal subjects, 83 schizophrenic probands, and 87 of their unaffected siblings was investigated, all of whom had measures of prefrontal "noise" estimated from event-related electroencephalogram during an auditory oddball task. The val(108/158)met genotype was significantly associated with prefrontal "noise"; homozygous Val-carriers had greatest prefrontal "noise" values; odds ratio (OR) = 2.37 (95% confidence interval [CI] 1.37-4.10), p = 003. The genotype-phenotype association was stronger when only considering male subjects with an OR = 3.37 (95% CI: 1.63-6.98), p = 002. The results suggest that COMT genotype impacts the level of prefrontal physiologic "noise." |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 185 | Psychiatr. Genet. 2006 Jun 16: 117-24 |
| PMID | 16691129 |
| Title | Catechol-O-methyltransferase Val158Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups. |
| Abstract | A single-nucleotide polymorphism of the gene coding for catechol-O-methyltransferase (COMT Val(158)Met) is associated with prefrontal-dependent task performance in schizophrenia. We evaluated the relationship of the COMT genotype with diagnostic status and cognitive performance in schizotypal personality disorder. Unmedicated outpatients with schizotypal personality disorder (SPD; n = 67) and non-schizotypal personality disorder (NSPD; n = 154) by DSM-III-R, and normal control (NC; n = 60) participants were genotyped at the COMT Val(158)Met locus. Of these, 98 Caucasians (23 SPD, 52 NSPD and 23 NC) performed a brief neurocognitive battery: Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test (CVLT), Visuospatial Working Memory (DOT) and Visual Delayed Recall (Wechsler Memory Scale Visual Reproduction, WMS-VR). Allele distribution was not significantly different in the full sample (by chi(2)) for the SPD group compared with either the NC or combined NC/NSPD groups. In analyses of variance of Caucasian individuals, the SPD group performance met or approached significantly worse performance than NC, NSPD or both groups, on the PASAT, CVLT and WMS-VR. In regression analyses of cognitive performance, the COMT genotype was significantly associated with performance on WCST and PASAT, independent of diagnosis, with the Val/Val genotype associated with the worse performance. (1) Allelic variation in COMT activity is unrelated to the diagnosis of SPD in this sample. (2) Individuals with SPD exhibit multiple deficits in prefrontal and temporal lobe-dependent tasks. (3) The COMT genotype is related to performance on prefrontal cortex-dependent tasks and may contribute to the deficit in prefrontal-dependent memory processes in SPD as it does in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 186 | Schizophr. Res. 2006 Jun 84: 253-71 |
| PMID | 16632332 |
| Title | Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. |
| Abstract | Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 187 | Schizophr Bull 2006 Jan 32: 9-16 |
| PMID | 16319375 |
| Title | Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. |
| Abstract | It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 188 | Bipolar Disord 2006 Apr 8: 124-32 |
| PMID | 16542182 |
| Title | The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder. |
| Abstract | Bipolar disorder is associated with deficits in cognitive functioning. The etiology of cognitive impairment in bipolar disorder may relate to both genetic and environmental factors. A valine/methionine polymorphism of the catechol O-methyltransferase gene at amino acid 158 (COMT Val158Met polymorphism) has been identified as a risk factor for cognitive impairment in schizophrenia. Serological evidence of infection with herpes simplex virus type 1 (HSV-1) has also been identified as a risk factor for cognitive impairment in bipolar disorder. We used Taqman technology to measure COMT Val158Met alleles in 107 individuals with bipolar disorder and in 95 controls. We also measured antibodies to HSV-1 in sera obtained from the same individuals. Cognitive functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and the Letter-Number Sequencing Test. The effects of the COMT Val158Met polymorphism and antibodies to HSV-1 on cognitive functioning were analyzed with multinomial logistic regressions. The COMT Val158Val genotype and serological evidence of infection with HSV-1 are independent risk factors for cognitive impairment in individuals with bipolar disorder, particularly in the domains of immediate and delayed memory. Individuals with bipolar disorder with the COMT158 Val/Val genotype and serological evidence of HSV-1 infection were more than 85 times more likely to be in the lowest quintile of cognitive functioning when compared with the highest quintile when controlling for potential confounding variables such as symptom severity and education. Control individuals did not display this association. Both the COMT Val158Met polymorphism and serological evidence of HSV-1 infection affect cognitive functioning in individuals with bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 189 | NeuroRx 2006 Jan 3: 117-30 |
| PMID | 16490418 |
| Title | Imaging genomics and response to treatment with antipsychotics in schizophrenia. |
| Abstract | Recent important advancements in genomic research have opened the way to new strategies for public health management. One of these questions pertains to how individual genetic variation may be associated with individual variability in response to drug treatment. The field of pharmacogenetics may have a profound impact on treatment of complex psychiatric disorders like schizophrenia. However, pharmacogenetic studies in schizophrenia have produced conflicting results. The first studies examined potential associations between clinical response and drug receptor genes. Subsequent studies have tried to use more objective phenotypes still in association with drug receptor genes. More recently, other studies have sought the association between putative causative or modifier genes and intermediate phenotypes. Thus, conflicting results may be at least in part explained by variability and choice of the phenotype, by choice of candidate genes, or by the relatively little knowledge about the neurobiology of this disorder. We propose that choosing intermediate phenotypes that allow in vivo measurement of specific neuronal functions may be of great help in reducing several of the potential confounds intrinsic to clinical measurements. Functional neuroimaging is ideally suited to address several of these potential confounds, and it may represent a powerful strategy to investigate the relationship between behavior, brain function, genes, and individual variability in the response to treatment with antipsychotic drugs in schizophrenia. Preliminary evidence with potential susceptilibity genes such as COMT, DISC1, and GRM3 support these assumptions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 190 | NeuroRx 2006 Jan 3: 97-105 |
| PMID | 16490416 |
| Title | Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics. |
| Abstract | Catechol-O-methyltransferase (COMT) is a gene involved in the degradation of dopamine and may both increase susceptibility to develop schizophrenia and affect neuronal functions involved in working memory. A common variant of the COMT gene (val(108/158)met) has been widely reported to affect pre-frontally mediated working memory function, with the high-activity val allele associated with poorest performance across a number of tests sensitive to updating and target detection. Pharmacological manipulations of COMT val(108/158)met also have reliably produced alterations in cognitive function, in line with an inverted U function of prefrontal dopamine signaling. Furthermore, there is accumulating evidence that COMT val(108/158)met genotype may influence the cognitive response to antipsychotic treatment in schizophrenia patients, with met allele load predicting the greatest improvement with medication. Recently, other single-nucleotide polymorphisms (SNPs) across the COMT gene have emerged as possible risk alleles for schizophrenia, although little is known about whether they affect prefrontal cognition in a manner similar to COMT val(108/158)met. Preliminary evidence suggests a modest role for a SNP in the 5' region of the gene on select tests of attention and target detection. Haplotype effects also may account for a modest percentage of the variance in test performance, and are an important area for future study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 191 | BMC Med. Genet. 2006 -1 7: 10 |
| PMID | 16483362 |
| Title | The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression. |
| Abstract | The COMT gene is located on chromosome 22q11, a region strongly implicated in the aetiology of several psychiatric disorders, in particular schizophrenia. Previous research has suggested that activity and expression of COMT is altered in schizophrenia, and is mediated by one or more polymorphisms within the gene, including the functional Val158Met polymorphism. In this study we examined the expression levels of COMT mRNA using quantitative RT-PCR in 60 post mortem cerebellum samples derived from individuals with schizophrenia, bipolar disorder, depression, and no history of psychopathology. Furthermore, we have examined the methylation status of two CpG sites in the promoter region of the gene. We found no evidence of altered COMT expression or methylation in any of the psychiatric diagnoses examined. We did, however, find evidence to suggest that genotype is related to COMT gene expression, replicating the findings of two previous studies. Specifically, val158met (rs165688; Val allele) rs737865 (G allele) and rs165599 (G allele) all showed reduced expression (P < 0.05). Finally, we observe a strong sexual dimorphism in COMT expression, with females exhibiting significantly greater levels of COMT mRNA. The expression of COMT does not appear to be altered in the cerebellum of individuals suffering from schizophrenia, bipolar disorder or depression, but does appear to be influenced by single nucleotide polymorphisms within the gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 192 | Biochemistry 2006 Feb 45: 2178-88 |
| PMID | 16475806 |
| Title | The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures. |
| Abstract | The human gene for catechol O-methyltransferase (COMT) contains a common polymorphism that results in substitution of methionine (M) for valine (V) at residue 108 of the soluble form of the protein. While the two proteins have similar kinetic properties, 108M COMT loses activity more rapidly than 108V COMT at 37 degrees C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 degrees C. The 108M allele has been associated with increased risk for breast cancer, obsessive-compulsive disorder, and aggressive and highly antisocial manifestations of schizophrenia. In the current work, we have constructed homology models for both human COMT polymorphs and performed molecular dynamics simulations of these models at 25, 37, and 50 degrees C to explore the structural consequences of the 108V/M polymorphism. The simulations indicated that replacing valine with the larger methionine residue led to greater solvent exposure of residue 108 and heightened packing interactions between M108 and helices alpha2, alpha4 (especially with R78), and alpha5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 A away, leading to a loosening of the active site. At physiological temperature, 108M COMT sampled a larger distribution of conformations than 108V. 108M COMT was more prone to active-site distortion and had greater overall, and SAM binding site, solvent accessibility than 108V COMT at 37 degrees C. Similar structural perturbations were observed in the 108V protein only at 50 degrees C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 193 | Pharmacogenet. Genomics 2006 Feb 16: 111-7 |
| PMID | 16424823 |
| Title | Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms. |
| Abstract | Tardive dyskinesia (TD) is an antipsychotic induced side effect observed in 20-30% of schizophrenia subjects on long-term typical antipsychotic treatment. We tested the possible association of 24 polymorphisms from six dopaminergic genes: namely, dopamine receptors D1, D2, D3, D4; the dopamine transporter (DAT); and the catalyzing enzyme catechol-O-methyltransferase (COMT), with TD. Multiple SNP/VNTR markers from candidate genes were analyzed using suitable approaches and allelic, genotypic and haplotypic associations were tested. 120 bp duplication marker, 1.2 kb upstream from initiation codon of DRD4 gene showed a significant genotypic association [chi2 = 9.29, P = 0.009; OR (95% CI) = 0.52 (0.31-0.86) for genotype 120 dup/120 dup]. In the COMT gene, a significant allelic [chi2 = 13.87, P = 0.0002] as well as genotypic association [chi2 = 16.08, P = 0.0003; OR (95% CI) = 0.24 (0.11-0.55) for genotype GG] was observed with the 408 C>G (exon 4) single nucleotide polymorphism and a significant genotypic association [chi2 = 6.32, P = 0.04; OR (95% CI) = 0.50 (0.33-0.92) for genotype GG] was observed with 472 G > A (exon 4, Val 158 Met) SNP. 120 bp dup-T-repeat 3 in DRD4 and G-C-A-insC in COMT genes were observed to be TD associated haplotypes. Our study presents a detailed analysis of the possible role of dopaminergic genes in the genesis of TD. DRD4 and COMT genes were observed to be the most important candidates in North Indian schizophrenia subjects. These suggestive associations need to be investigated in replicate studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 194 | Brain 2006 Feb 129: 399-410 |
| PMID | 16330500 |
| Title | The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia. |
| Abstract | The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 195 | Neurosci. Lett. 2006 Jan 393: 170-3 |
| PMID | 16233957 |
| Title | Analysis of an association between the COMT polymorphism and clinical symptomatology in schizophrenia. |
| Abstract | Based on their metabolic inactivation of dopamine and norepinephrine, genes encoding the catechol-O-methyltransferase (COMT) enzyme are appropriate candidates to consider in the pathogenesis of schizophrenia. COMT enzyme activity is regulated by a common polymorphism causing substantial variations in enzymatic activity, and evidence for allelic or genotypic association with cognitive and behavioral features of schizophrenia has been noted. Since the role of COMT in schizophrenia remains inconclusive, we determined whether any association exists between COMT genotypes and clinical symptomatology in a large cohort of schizophrenia subjects. DNA was extracted from peripheral blood in 111 patients with DSM-IV criteria schizophrenia (77 M, 34 F) and genotyped for COMT polymorphisms. Subjects were also were rated by means of the PANSS and the CGI. No association was found between COMT genotype or allele frequency and gender. No associations were observed between COMT and CGI or PANSS scores. Our findings do not support hypotheses regarding associations between COMT polymorphisms and clinical state in schizophrenia, contrary to other studies suggesting involvement of the COMT polymorphism with schizophrenia phenotype. Thus, while speculative, it may be suggested that a modifying gene may be required in order for the COMT polymorphism to manifest at the clinical level in schizophrenia with one set of susceptibility genes being more sensitive to COMT enzyme variability than others. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 196 | World J. Biol. Psychiatry 2006 -1 7: 238-45 |
| PMID | 17071544 |
| Title | Association study of COMT gene Val158Met polymorphism with auditory P300 and performance on neurocognitive tests in patients with schizophrenia and their relatives. |
| Abstract | A number of studies have reported an association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and neuropsychological traits in patients with schizophrenia, their relatives and healthy controls, with the Met allele carriers performing better on neurocognitive tasks than those with the Val allele. But the association was not confirmed in all studies. The present paper was aimed at further investigation of the COMT gene relationship with some neurocognitive traits, assessing mainly working and verbal memory, and to P300 event-related potentials (auditory oddball). A total sample of 319 individuals, including schizophrenic patients, their relatives and controls, was studied. No significant differences in performance of neurocognitive tasks were found by Val158Met genotypes. An association was observed between the Met/Met genotype and higher amplitude in centro-parietal area in relatives. Factors that could explain the non-replication of previous studies on the COMT gene polymorphism and neurocognitive traits are discussed. We suggest here that (1) Val158Met polymorphism rather exerts a modifying influence on brain activation in general than impacts directly on performance of the particular neurocognitive test, and (2) P300 amplitude seems to be a correlate of this activation reflecting, along with information processing, the subject's affective and personality features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 197 | Hum. Mol. Genet. 2006 Sep 15: 2804-12 |
| PMID | 16905560 |
| Title | RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. |
| Abstract | Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 198 | Schizophr. Res. 2006 Sep 86: 1-14 |
| PMID | 16842972 |
| Title | Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. |
| Abstract | Over 130 genes have been associated with schizophrenia in genetic studies. None of these has reached a sufficient level of confidence to be accepted as a universal susceptibility gene and problems of replicability suggest that many may be false positives. Nevertheless, these genes can be grouped into distinct families related to glutamate transmission (in particular related to NMDA receptor function), the control of synaptic plasticity, dopaminergic transmission, oxidative stress, glutathione and quinone metabolism and oligodendrocyte viability. These families mirror the processes disrupted in the schizophrenic brain and certain gene families can be linked together to form a clearly defined signalling cascade involved in the phenomenon of NMDA receptor-dependent long-term potentiation and synaptic plasticity, that may be interconnected with oligodendrocyte and oxidative stress-related pathways. Many of the protein products of these genes interact with each other, forming complex integrated networks. Certain high-interest genes (for example DISC1, NRG1, COMT) may exert multiple effects on different areas of these pathways, while others exert more specific effects on certain branches. The convergence of a large number of genes on a definable signaling network raises the possibility of numerous interactions between gene candidates, and suggests that a targeted multigenic pathway approach would be useful in gene association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 199 | Hum. Genet. 2006 Sep 120: 160-70 |
| PMID | 16783572 |
| Title | A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia. |
| Abstract | Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 200 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jul 141B: 504-12 |
| PMID | 16741933 |
| Title | Lack of influence of COMT and NET genes variants on executive functions in schizophrenic and bipolar patients, their first-degree relatives and controls. |
| Abstract | Abnormal dopaminergic function in the prefrontal cortex (PFC) may be a key factor in the etiopathogeny of schizophrenia and bipolar disorder. Both schizophrenic and bipolar subjects have executive functions (EF) deficits, thought to reflect abnormal PFC function. The main inactivation pathways for dopamine in the PFC are enzymatic cleavage by the Carboxy-O-Methyl-Transferase (COMT) and reuptake by the nor-epinephrine transporter (NET). Our aim in this study was to replicate previous studies that investigated influence of the COMT genotype on EF in schizophrenic subjects, their relatives and controls and extend their scope by including bipolar patients, and their relatives and by exploring NET gene polymorphisms influence on executive performances. We investigated one functional polymorphism of the COMT gene and two polymorphisms of the NET gene. EF were assessed by means of the Trail Making Test (TMT) and the Wisconsin Card Sorting Test (WCST). We assessed the effect of each of the three genotypes on EF for the whole sample (N = 318) and separately in schizophrenic (N = 66), bipolar (N = 94) and healthy subjects (i.e., relatives and controls N = 158). Separate analyses were performed because of the presence, in patients samples, of potentially confounding factors, especially medication. Genotype had no significant effect on the cognitive measures in any of the analyses (for the two EF measures, the three polymorphisms, and the four groups). In our sample we found no evidence in favor of a major effect of COMT or NET polymorphisms on the two tests of EF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 201 | Biol. Psychiatry 2006 Sep 60: 578-84 |
| PMID | 16730334 |
| Title | Prefrontal electrophysiologic "noise" and catechol-O-methyltransferase genotype in schizophrenia. |
| Abstract | Increased variability of stimulus-induced prefrontal electromagnetic activity ("noise") has been associated with genetic risk for schizophrenia. On the basis of animal experiments and computational models, we have predicted that this prefrontal "noise" phenotype would be related to variation in prefrontal dopamine (DA) signaling, which itself might be abnormal in schizophrenia. In the present study, the effect of a functional single nucleotide polymorphism (val(108/158)met) within the catechol-O-methyltransferase (COMT) gene on prefrontal "noise" was examined, because the COMT enzyme is involved in cortical synaptic dopamine metabolism and weakly predictive of risk for schizophrenia. A Caucasian sample comprising 112 unrelated normal subjects, 83 schizophrenic probands, and 87 of their unaffected siblings was investigated, all of whom had measures of prefrontal "noise" estimated from event-related electroencephalogram during an auditory oddball task. The val(108/158)met genotype was significantly associated with prefrontal "noise"; homozygous Val-carriers had greatest prefrontal "noise" values; odds ratio (OR) = 2.37 (95% confidence interval [CI] 1.37-4.10), p = 003. The genotype-phenotype association was stronger when only considering male subjects with an OR = 3.37 (95% CI: 1.63-6.98), p = 002. The results suggest that COMT genotype impacts the level of prefrontal physiologic "noise." |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 202 | Brain 2006 Feb 129: 399-410 |
| PMID | 16330500 |
| Title | The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia. |
| Abstract | The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 203 | Neurosci. Lett. 2006 Dec 409: 205-9 |
| PMID | 17029783 |
| Title | COMT genotype, gender and cognition in community-dwelling, older adults. |
| Abstract | A common polymorphism (Val158Met) in the gene encoding for the catechol-O-methyltransferase (COMT) enzyme has been associated with differences in prefrontal cognitive function in schizophrenic patients and healthy adults. While several studies indicate that the Met allele is associated with better performance on measures of executive function, working memory and verbal fluency, results have been inconsistent. Furthermore, fewer studies have investigated this relationship in older adults, a group known to experience impairments in prefrontal cognitive functions. Additionally, findings vary according to the gender distribution of study participants. We examined whether COMT genotype interacted with gender to impact cognition in a cohort of 163 healthy, older adults. Memory, verbal ability and areas of prefrontal cognitive function, including attention, speed-of-processing, and executive function, were assessed. We found no significant association between COMT genotype and any cognitive measure. However, gender interacted with COMT genotype to impact cognitive performance. Males homozygous for the Val allele performed better than both the Val/Met and Met/Met groups on measures of delayed recall. Heterozygous women performed better than their homozygous counterparts on the measure of verbal ability. These findings suggest that gender may be an important variable in consideration of the impact of COMT on cognition. Further, when gender is taken into consideration, any negative impact of COMT genotype may extend to cognitive domains other than those associated with prefrontal regions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 204 | Psychiatr. Genet. 2006 Jun 16: 117-24 |
| PMID | 16691129 |
| Title | Catechol-O-methyltransferase Val158Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups. |
| Abstract | A single-nucleotide polymorphism of the gene coding for catechol-O-methyltransferase (COMT Val(158)Met) is associated with prefrontal-dependent task performance in schizophrenia. We evaluated the relationship of the COMT genotype with diagnostic status and cognitive performance in schizotypal personality disorder. Unmedicated outpatients with schizotypal personality disorder (SPD; n = 67) and non-schizotypal personality disorder (NSPD; n = 154) by DSM-III-R, and normal control (NC; n = 60) participants were genotyped at the COMT Val(158)Met locus. Of these, 98 Caucasians (23 SPD, 52 NSPD and 23 NC) performed a brief neurocognitive battery: Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test (CVLT), Visuospatial Working Memory (DOT) and Visual Delayed Recall (Wechsler Memory Scale Visual Reproduction, WMS-VR). Allele distribution was not significantly different in the full sample (by chi(2)) for the SPD group compared with either the NC or combined NC/NSPD groups. In analyses of variance of Caucasian individuals, the SPD group performance met or approached significantly worse performance than NC, NSPD or both groups, on the PASAT, CVLT and WMS-VR. In regression analyses of cognitive performance, the COMT genotype was significantly associated with performance on WCST and PASAT, independent of diagnosis, with the Val/Val genotype associated with the worse performance. (1) Allelic variation in COMT activity is unrelated to the diagnosis of SPD in this sample. (2) Individuals with SPD exhibit multiple deficits in prefrontal and temporal lobe-dependent tasks. (3) The COMT genotype is related to performance on prefrontal cortex-dependent tasks and may contribute to the deficit in prefrontal-dependent memory processes in SPD as it does in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 205 | Schizophr. Res. 2007 Sep 95: 253-5 |
| PMID | 17644310 |
| Title | COMT Val158Met polymorphism predicts negative symptoms response to treatment with olanzapine in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 206 | Br J Psychiatry 2007 Nov 191: 402-7 |
| PMID | 17978319 |
| Title | Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. |
| Abstract | Genetic variations might modify associations between schizophrenia and cannabis or tobacco use. To examine whether variants within the cannabinoid receptor (CNR1) and alpha(7) nicotinic receptor (CHRNA7) genes are associated with schizophrenia, and whether these effects vary according to cannabis or tobacco use. We also examined a putative interaction between cannabis and Val(158)Met within the catechol-O-methyltransferase gene (COMT). Genotype effects of CHRNA7 and CNR1were studied in a case-control sample of 750 individuals with schizophrenia and 688 controls, with interactions for these genes studied in small subsamples. A case-only design of 493 ofthe schizophrenia group was used to examine interactions between cannabis use and COMT. There was no evidence of association between schizophrenia and CNR1 (OR=0.97, 95% CI 0.82-1.13) or CHRNA7 (OR=1.07, 95% CI 0.77-1.49) genotypes, or of interactions between tobacco use and CHRNA7, or cannabis use and CNR1or COMT genotypes. Neither CNR1 nor CHRNA7 variation appears to alter the risk of schizophrenia. Furthermore, our results do not support the presence of different effects of cannabis use on schizophrenia according to variation within COMT. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 207 | Psychiatr. Genet. 2007 Dec 17: 344-6 |
| PMID | 18075475 |
| Title | Irritable assault and variation in the COMT gene. |
| Abstract | Aggression is associated with the 'low' activity allele (Met) of the functional Val158Met polymorphism among people with schizophrenia spectrum disorders relative to the 'high' activity (Val) allele. We examined this polymorphism in a sample of 112 people with axis II personality disorders. Participants completed the Buss Durkee Hostility Inventory. Two single nucleotide polymorphisms in the COMT gene were genotyped in these participants classified as 'white' according to US Census Bureau definitions. We failed to observe an association between the Val158Met allele and aggression but observed an association between self-reported aggression and the G allele of a biallelic polymorphism located in the 3'' UTR (rs16559). This allele is less prevalent among schizophrenics and is associated with lower COMT expression in the brain. These findings provide limited support for a role of COMT in modulating aggressive behavior, and are extended to people with personality disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 208 | Behav. Brain Res. 2007 Nov 183: 236-9 |
| PMID | 17707921 |
| Title | Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice. |
| Abstract | Catechol-O-methyltransferase (COMT) inactivates dopamine in prefrontal cortex and is associated clinically with a schizophrenia endophenotype. Using an ethologically based approach, the phenotype of mice with heterozygous COMT deletion was characterised by decreased rearing with increased sifting and chewing. Heterozygous COMT deletion is associated with a distinctive phenotype. This differs from that which we have reported previously for heterozygous deletion of the schizophrenia risk gene neuregulin-1. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 209 | Proc. Natl. Acad. Sci. U.S.A. 2007 Jul 104: 12536-41 |
| PMID | 17636131 |
| Title | Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. |
| Abstract | Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that these genes influence prefrontal physiological signal-to-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontal-parietal coupling on the background of COMT Val-homozygous genotype. Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 210 | Schizophr. Res. 2007 Nov 96: 87-92 |
| PMID | 17601704 |
| Title | The catechol O-methyltransferase Val158Met polymorphism is not associated with broad-based cognitive functioning in schizophrenia. |
| Abstract | A valine/methionine polymorphism of the catechol O-methyltransferase gene at the nucleotide which encodes amino acid val or met at position 158 in the protein (COMT Val158Met polymorphism) has been associated with deficits in executive functioning in schizophrenia in some studies. The association between the COMT polymorphism and other cognitive domains has been the focus of only limited investigation. We measured COMT Val158Met genotypes in N=364 individuals with schizophrenia. Cognitive functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We employed univariate and multivariate analyses of variance to determine the association between COMT genotypes and the RBANS index and individual test scores. There was no significant association between the COMT Val158Met genotypes and any of the RBANS index or individual test scores measured in either univariate or multivariate analyses (all p>.3). Based on the results in our sample, the catechol O-methyltransferase Val158Met polymorphism is not associated with broad-based cognitive functioning in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 211 | Hum Psychopharmacol 2007 Jun 22: 211-5 |
| PMID | 17526059 |
| Title | Catechol-O-methyltransferase val108/158met genotype and response to antipsychotic medication in schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) gene has been investigated as a possible candidate gene in schizophrenia. The most studied polymorphism has been the functional val108/158met polymorphism of this COMT gene. There is also some evidence that this polymorphism could be related to drug response to antipsychotics in schizophrenia. COMT enzyme inactivates dopamine and noradrenaline. Based mainly on the original dopamine theory of schizophrenia, our primary hypothesis was that the maintenance dose of antipsychotics would be higher in patients with the low activity COMT genotype. In this study we evaluated the current daily dosage of antipsychotics in 180 patients with schizophrenia in connection with the COMT genotype. We could not demonstrate any clearly significant effect of this particular COMT genotype in relation to the daily maintenance dosages of antipsychotics in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 212 | J Abnorm Psychol 2007 May 116: 306-12 |
| PMID | 17516763 |
| Title | COMT val158Met and executive control: a test of the benefit of specific deficits to translational research. |
| Abstract | The role of catechol-O-methyltransferase (COMT) val158met in prefrontal cortical deficits associated with the liability to schizophrenia remains controversial. This study evaluated 464 healthy adult participants using three measures of executive functions in working memory: a 3-back version of the N-back continuous performance task (CPT) and two variants of the AX-CPT. The interpretability of N-back performance was confounded by possible generalized deficits, whereas the AX variants included internal controls for uncovering specific deficits. There was no relationship between the COMT genotype and N-back performance, whereas val/val individuals had a specific deficit on a dot-pattern version of the AX-CPT. In this case, a specific executive function known as context processing appeared to be compromised. These data suggest that the interpretability gained by including task manipulations to uncover specific deficits can enhance associations between cognitive and genetic levels of analysis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 213 | J Neural Transm (Vienna) 2007 Sep 114: 1199-215 |
| PMID | 17514428 |
| Title | Which perspectives can endophenotypes and biological markers offer in the early recognition of schizophrenia? |
| Abstract | The early recognition of schizophrenia seems crucial; various studies relate a longer duration-of-untreated-psychosis to a worse prognosis. We give an overview over common psychopathological early recognition instruments (BSABS, CAARMS, SIPS, IRAOS, ERIraos). However, many clinical symptoms of prodromal schizophrenia stages are not sufficiently specific. Thus we review recent contributions of neuroimaging and electrophysiological as well as genetic studies: which new diagnostic perspectives offer endophenotypes (such as P300, P50 sensory gating, MMN, smooth pursuit eye movements; indicating a specific genetic vulnerability) together with a better understanding of schizophrenic pathophysiology (state-dependent biological markers, e.g. aggravated motor neurological soft signs during psychosis) in prodromal schizophrenia when still ambiguous clinical symptoms are present. Several examples (e.g. from COMT polymorphisms to working memory deficits) illustrate more specific underlying neuronal mechanisms behind behavioural symptoms. This way, a characteristic pattern of disturbed cerebral maturation might be distinguished in order to complement clinical instruments of early schizophrenia detection. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 214 | Neurosci. Res. 2007 Jul 58: 291-6 |
| PMID | 17482701 |
| Title | No associations exist between five functional polymorphisms in the catechol-O-methyltransferase gene and schizophrenia in a Japanese population. |
| Abstract | Catechol-O-methyltransferase (COMT) is one of the enzymes that degrade catecholamine neurotransmitters including dopamine. The COMT gene is located on 22q11.2, a common susceptibility locus for schizophrenia. Therefore, COMT is a strong functional and positional candidate gene for schizophrenia. A common functional polymorphism (rs4680, Val158Met) has been extensively tested for an association with schizophrenia, but with conflicting results. Recent studies indicate that if COMT is implicated in susceptibility to schizophrenia, this cannot be wholly accounted for by the Val158Met polymorphism. To assess this view, the authors conducted a case-control association study (399 patients with schizophrenia and 440 control subjects) for five functional polymorphisms (rs2075507, rs737865, rs6267, rs4680 and rs165599) in Japanese subjects. There were no significant associations found between the polymorphisms or haplotypes of COMT and schizophrenia. The present study shows that these five functional COMT polymorphisms do not play a major role in conferring susceptibility to schizophrenia in Japanese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 215 | Biol. Psychiatry 2007 Oct 62: 822-5 |
| PMID | 17448448 |
| Title | Effect of catechol O-methyltransferase val(158)met polymorphism on the p50 gating endophenotype in schizophrenia. |
| Abstract | Studies have implicated prefrontal dopamine in cortical information filtering. Deficit in stimulus filtering, an endophenotype of schizophrenia, can be demonstrated using the auditory P50 paired-click gating paradigm. The role of prefrontal dopamine on P50 gating was investigated, using catechol-O-methyltransferase (COMT) valine (val)(158)methionine (met) polymorphism as a predictor of prefrontal dopamine activity. Twenty-five comparison and 42 schizophrenia subjects underwent P50 gating measurement and COMT genotyping. In the combined sample, COMT polymorphism accounted for a unique 10% of gating variance (p = .02), after variance due to diagnosis, smoking status, and antipsychotic use was removed. Valine homozygous individuals exhibited the greatest gating deficit. Valine homozygous individuals are more likely to have gating deficits, supporting COMT as a genetic determinant of the P50 endophenotype, as well as a role for prefrontal dopamine in auditory filtering. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 216 | Hum Brain Mapp 2007 Jun 28: 533-42 |
| PMID | 17427209 |
| Title | Abnormal cortical activation during response inhibition in 22q11.2 deletion syndrome. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is a well-known genetic risk factor for schizophrenia. The catechol-O-methyltransferase (COMT) gene falls within the 22q11.2 minimal critical region of the deletion. Brain activity, as measured by functional magnetic resonance imaging (fMRI) during a Go/NoGo, response inhibition task was assessed in adolescents with 22q11.2DS (n = 13), typically developing (TD) controls (n = 14), and controls with developmental disability (DD, n = 9). Subjects with 22q11.2DS were also genotyped for the COMT Met/Val polymorphism. Groups did not differ on task performance. However, compared to both control groups, the 22q11.2DS group showed greater brain activation within left parietal regions. Comparison of brain activation between 22q11.2DS Met and Val subgroups revealed significantly increased activation (Met>Val) in the cingulate but not the dorsolateral prefrontal cortex. These preliminary findings suggest that adolescents with 22q11.2DS compensate for executive dysfunction via recruitment of parietal regions. Further, the COMT Met subgroup of 22q11.2DS may recruit additional cingulate activation for tasks requiring attention and inhibition. 22q11.2DS is a unique model for learning about the deleterious effects of decreased dosage of the COMT gene on brain function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 217 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jun 144B: 570-3 |
| PMID | 17427186 |
| Title | Association analysis of COMT polymorphisms and schizophrenia in a Chinese Han population: a case-control study. |
| Abstract | schizophrenia is a common disease with complex mode of inheritance; great efforts have been made to identify the susceptible genes. Catechol-O-methyltransferase (COMT) gene has long been considered as a candidate gene mainly because of two reasons: First, it encodes a key dopamine catabolic enzyme. Second, it maps to the velocardiofacial syndrome (VCFS) region of chromosome 22q11, which is associated with schizophrenia predisposition. Numerous case-control and family-based studies have been conducted, majority of them focused on a functional Val/Met polymorphism (rs4680). Unfortunately, these studies have produced conflicting results. In a previous report, Shifman et al. found a three-marker haplotype (rs737865-rs4680-rs165599) that showed significant association with schizophrenia. In this study, we try to replicate their findings in Chinese Han population and failed to find any associations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 218 | Eur. Psychiatry 2007 Jul 22: 276-81 |
| PMID | 17419009 |
| Title | Role of the COMT gene Val158Met polymorphism in mental disorders: a review. |
| Abstract | The Val158Met polymorphism of the COMT gene is functional, easily detectable, and significantly related to metabolism of catecholamines, which underlie pathogenesis of a significant number of mental disorders. Evidence for the role of this polymorphism in schizophrenia, substance dependence, bipolar disorder, obsessive-compulsive disorder, anorexia nervosa and attention deficit hyperactivity disorder is summed up in this review article. The results make it unlikely that the COMT gene plays an important role in these mental disorders, although a minor effect can not be excluded. Future studies on the COMT gene in mentally ill subjects should be stratified by clinical subtypes of the disorder, gender and ethnicity. Studies of endophenotypes instead of the complex disorder seem to be another promising research strategy. Gene-gene and gene-environment interactions should also be considered. The COMT gene is probably not "a gene for" any mental disorder, but the Val158Met polymorphism appears to have pleiotropic effects on human behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 219 | Mol. Psychiatry 2007 May 12: 502-9 |
| PMID | 17325717 |
| Title | Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. |
| Abstract | The catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n=1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d=0.29; 95% confidence interval (CI) 0.02-0.55; P=0.03), but this was not supported in the patient sample (d=-0.07; 95% CI -0.40 to 0.26; P=0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val(158)Met genotype and executive function in healthy individuals but not in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 220 | Schizophr. Res. 2007 Feb 90: 104-7 |
| PMID | 17113268 |
| Title | DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability. |
| Abstract | The C957T polymorphism in the dopamine D2 receptor (DRD2) gene and the Val158Met polymorphism in the Catechol-O-Methyl-Transferase (COMT) gene affect dopamine transmission and have been found to be associated with schizophrenia. Since DRD2 in mice and the COMT gene in humans modulate working memory, we examined the relationship and possible interaction of both polymorphisms to working memory performance in 188 healthy adults. Subjects having the DRD2 C/C allele showed the poorest performance in a word serial position test. Moreover, the effect of the C957T genotype was strengthened when interaction with the COMT Val158Met polymorphism was included in the analysis. We propose that an interaction of the DRD2 C957T and COMT Val158Met may be involved in the generation of some working memory deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 221 | PLoS ONE 2007 -1 2: e1369 |
| PMID | 18159252 |
| Title | Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/Akt-dependent pathway: potential implications for schizophrenia and cancer. |
| Abstract | Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer. Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063). Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 222 | Psychiatr. Genet. 2007 Dec 17: 344-6 |
| PMID | 18075475 |
| Title | Irritable assault and variation in the COMT gene. |
| Abstract | Aggression is associated with the 'low' activity allele (Met) of the functional Val158Met polymorphism among people with schizophrenia spectrum disorders relative to the 'high' activity (Val) allele. We examined this polymorphism in a sample of 112 people with axis II personality disorders. Participants completed the Buss Durkee Hostility Inventory. Two single nucleotide polymorphisms in the COMT gene were genotyped in these participants classified as 'white' according to US Census Bureau definitions. We failed to observe an association between the Val158Met allele and aggression but observed an association between self-reported aggression and the G allele of a biallelic polymorphism located in the 3'' UTR (rs16559). This allele is less prevalent among schizophrenics and is associated with lower COMT expression in the brain. These findings provide limited support for a role of COMT in modulating aggressive behavior, and are extended to people with personality disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 223 | J Neural Transm (Vienna) 2007 Sep 114: 1199-215 |
| PMID | 17514428 |
| Title | Which perspectives can endophenotypes and biological markers offer in the early recognition of schizophrenia? |
| Abstract | The early recognition of schizophrenia seems crucial; various studies relate a longer duration-of-untreated-psychosis to a worse prognosis. We give an overview over common psychopathological early recognition instruments (BSABS, CAARMS, SIPS, IRAOS, ERIraos). However, many clinical symptoms of prodromal schizophrenia stages are not sufficiently specific. Thus we review recent contributions of neuroimaging and electrophysiological as well as genetic studies: which new diagnostic perspectives offer endophenotypes (such as P300, P50 sensory gating, MMN, smooth pursuit eye movements; indicating a specific genetic vulnerability) together with a better understanding of schizophrenic pathophysiology (state-dependent biological markers, e.g. aggravated motor neurological soft signs during psychosis) in prodromal schizophrenia when still ambiguous clinical symptoms are present. Several examples (e.g. from COMT polymorphisms to working memory deficits) illustrate more specific underlying neuronal mechanisms behind behavioural symptoms. This way, a characteristic pattern of disturbed cerebral maturation might be distinguished in order to complement clinical instruments of early schizophrenia detection. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 224 | J. Alzheimers Dis. 2007 Aug 12: 73-92 |
| PMID | 17851196 |
| Title | Genetics of Alzheimer's disease. A rapidly evolving field. |
| Abstract | Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 225 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 226 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 227 | J Neural Transm (Vienna) 2007 Feb 114: 255-9 |
| PMID | 16897602 |
| Title | Interaction between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in age at onset and clinical symptoms in schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) gene is one of the candidate genes for schizophrenia because it codes an enzyme that participates in the metabolic inactivation of dopamine and noradrenaline and a limiting factor of dopamine metabolism in the prefrontal cortex. COMT gene lies on chromosome 22q11.2, which has been associated with schizophrenia susceptibility. A single-nucleotide polymorphism of COMT gene at position 108/158 results in an amino acid substitution from valine (val) to methionine (met), which modifies its enzymatic activity and may change the brain morphology and expressional behaviors. On the other hand, brain-derived neurotrophic factor (BDNF) plays a critical role in the development of mesolimbic dopaminergic- related systems. BDNF also contains a functional single-nucleotide polymorphism at codon 66 (Val66Met) of its prodomain and this polymorphism is responsible for schizophrenia susceptibility. In this study, we first investigated the relationship between COMT Val108/158Met polymorphism and age at onset as well as levels of clinical symptoms in 158 of chronic schizophrenia inpatients and then we investigated the gene-by-gene interaction between COMT Val108/158Met polymorphism and BDNF Val66Met polymorphism with age- and sex-matched control subjects (n = 318). We concluded that the COMT Val108/158Met polymorphism was not related to either the onset at age or the levels of clinical symptoms after long-term antipsychotic treatment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 228 | J. Neurosci. 2007 Dec 27: 14190-8 |
| PMID | 18094258 |
| Title | The impact of catechol-O-methyltransferase and dopamine D4 receptor genotypes on neurophysiological markers of performance monitoring. |
| Abstract | Dynamic adaptations of one's behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints at the importance of the dopaminergic system for the regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMT Val allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 229 | Thromb. Haemost. 2007 Dec 98: 1226-31 |
| PMID | 18064318 |
| Title | Catechol-O-methyltransferase genotype is associated with plasma total homocysteine levels and may increase venous thrombosis risk. |
| Abstract | A disturbed methylation has been proposed as a mechanism via which homocysteine is associated with diseases like vascular disease, neural tube defects and mental disorders. Catechol-O-methyltransferase (COMT) is involved in the S-adenosylmethionine-dependent methylation of catecholamines and catecholestrogens and in this way contributes to homocysteine synthesis. COMT dysfunction has been related to schizophrenia and breast cancer. We hypothesized that COMT dysfunction by virtue of functional genetic polymorphisms may affect plasma total homocysteine (tHcy). Our primary objective was to study the association between common COMT polymorphisms and tHcy. Secondly, we evaluated these polymorphisms as a risk factor for recurrent venous thrombosis. We obtained genotype data from four polymorphisms in the COMT gene (rs2097603, rs4633, rs4680 [324G>A] and rs174699) from 401 population-based controls. We performed haplotype analysis to investigate the association between common haplotypes and tHcy. In addition, we assessed the rs4680 variant as a genetic risk factor in a case-control study on recurrent venous thrombosis (n = 169). We identified a common haplotype that was significantly associated with tHcy levels. This effect was largely explained by the rs4680 variant, resulting in an increase in tHcy of 10.4% (95% CI 0.01 to 0.21, p = 0.03) for 324AA compared with 324GG subjects. Interestingly, we found that the 324AA genotype was more common in venous thrombosis patients (OR 1.61 [95% CI 0.97 to 2.65], p = 0.06) compared to control subjects. We show that the COMT rs4680 variant modulates tHcy, and might be associated with venous thrombosis risk as well. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 230 | Cereb. Cortex 2007 Sep 17 Suppl 1: i171-81 |
| PMID | 17726000 |
| Title | Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. |
| Abstract | Cognitive deficits are critical determinants of schizophrenia morbidity. In this review, we offer a mechanistic perspective regarding schizophrenia-related changes observed in prefrontal cortical networks engaged in working memory. A body of earlier work converges on aberrations in putative macrocircuit stability and functional efficiency as the underlying pathophysiology of the cognitive deficits in schizophrenia. In parsing the dysfunctional prefrontal cortical dynamics of schizophrenia, recent functional magnetic resonance imaging and electoencephalography works suggest that in the context of reduced capacity for executive aspects of working memory, patients engage a larger network of cortical regions consistent with an interplay between reduced signal-to-noise components and the recruitment of compensatory networks. The genetic programming underlying these systems-level cortical interactions has been examined under the lens of certain schizophrenia susceptibility genes, especially catechol-o-methyltransferase (COMT) and GRM3. Variation in COMT, which presumably impacts on cortical dopamine signaling, translates into variable neural strategies for working memory and altering patterns of intracortical functional correlations. GRM3, which impacts on synaptic glutamate, interacts with COMT and exaggerates the genetic dissection of cortical processing strategies. These findings reveal novel insights into the modulation and parcellation of working memory processing in cortical assemblies and provide a mechanistic link between susceptibility genes and cortical pathophysiology related to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 231 | Mol. Psychiatry 2007 Sep 12: 854-69 |
| PMID | 17767149 |
| Title | Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. |
| Abstract | Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD(67)), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5' flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5' untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 232 | Neurosci. Behav. Physiol. 2007 Sep 37: 643-50 |
| PMID | 17763983 |
| Title | Interaction of dopamine system genes and cognitive functions in patients with schizophrenia and their relatives and in healthy subjects from the general population. |
| Abstract | Linkage between the DRD4 and COMT genes and cognitive measures characterizing verbal memory, executive functions, and associative processes was studied in 150 patients with schizophrenia, 83 of their relatives, and 118 mentally healthy subjects without any family history of psychoses, with the aim of detecting the main effects of the polymorphic markers -809G/A and -521C/T (DRD4) and Val158Met (COMT) when present individually and together. The group of patients showed a main effect for polymorphism -521C/T on verbal fluency and an effect of the interaction of this polymorphism and the COMT gene on this cognitive trait. The highest level of verbal fluency was seen among carriers of the Val/Val+CC and Met/Met+TT genotypes. In the combined group of unaffected individuals, the interaction of the COMT and DRD4 -521C/TT genotypes had an effect on the standardness of speech associations due to a decrease in the standardness of associations in carriers of the Met/Met+CC genotype. Finally, both patients and unaffected individuals showed an effect for the interaction between the COMT and DRD4 -809G/A genotypes on working memory. Patients and healthy subjects showed similar features: the highest values were seen in subjects homozygous for the Val and G alleles, while the lowest values were seen in homozygotes for the Met and A alleles. These data provide evidence for a relationship between the DRD4 and COMT genes and different aspects of executive functions and the absence of such a relationship in relation to verbal memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 233 | CNS Drugs 2007 -1 21: 535-57 |
| PMID | 17579498 |
| Title | Treatment of cognitive deficits associated with schizophrenia: potential role of catechol-O-methyltransferase inhibitors. |
| Abstract | In the last two decades, understanding of the dynamics of dopamine function in the prefrontal cortex and its role in prefrontal cortex physiology has opened up new avenues for therapeutic interventions in conditions in which prefrontal cortex function is compromised. Neuropsychological and imaging studies of prefrontal information processing have confirmed specific cognitive and neurophysiological abnormalities in individuals with schizophrenia. Because such findings are also observed in the healthy siblings of patients with schizophrenia, they may represent intermediate phenotypes related to schizophrenia susceptibility genes.Catechol-O-methyltransferase (COMT) represents an important candidate as a susceptibility gene for cognitive dysfunction in schizophrenia because of the unique role this enzyme plays in regulating prefrontal dopaminergic function. A functional COMT polymorphism (Val158Met) predicts performance in tasks of prefrontal executive function and the neurophysiological response measured with electroencephalography and functional magnetic resonance imaging in tasks assessing working memory. In fact, individuals with the Val/Val genotype, which encodes for the high-activity enzyme resulting in lower dopamine concentrations in the prefrontal cortex, perform less well and are less efficient physiologically than Met/Met individuals. These findings raise the possibility of new pharmacological interventions for the treatment of prefrontal cortex dysfunction and of predicting outcome based on COMT genotype. One strategy consists of the use of CNS-penetrant COMT inhibitors such as tolcapone. A second strategy is to increase extracellular dopamine concentrations in the frontal cortex by blocking the noradrenaline (norepinephrine) reuptake system, a secondary mechanism responsible for the disposal of dopamine from synaptic clefts in the prefrontal cortex. A third possibility involves the use of modafinil, a drug with an unclear mechanism of action but with positive effects on working memory in rodents. The potential of these drugs to improve executive cognitive function by selectively increasing dopamine load in the frontal cortex but not in subcortical territories, and the possibility that response to them may be modified by a COMT polymorphism, provides a novel genotype-based targeted pharmacological approach without abuse potential for the treatment of cognitive disorder in schizophrenia and in other conditions involving prefrontal cortex dysfunction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 234 | Bipolar Disord 2007 Jun 9: 370-6 |
| PMID | 17547583 |
| Title | COMT genotype increases risk for bipolar I disorder and influences neurocognitive performance. |
| Abstract | Bipolar disorder (BPD) is an affective disorder characterized by episodes of depression and mania. Cognitive impairment in patients with BPD is common and recent data suggest that it may represent a trait-like feature of the illness, as it persists during periods of wellness and co-segregates in families of bipolar patients. This suggests an underlying genetic predisposition towards cognitive impairment in patients with BPD; however, there have been few studies investigating the effects of candidate genes on this symptom domain. The catechol-O-methyl transferase (COMT) gene is located on chromosome 22q11 and is involved in the metabolism of dopamine and norepinephrine. A large body of evidence suggests that COMT is associated with cognitive performance in patients with schizophrenia and in healthy volunteers but there have been no reports of its relationship to cognition in BPD. We genotyped 52 Caucasian bipolar I probands and 102 Caucasian healthy controls across four single nucleotide polymorphisms (SNPs) within the COMT gene and administered a cognitive screening battery. We first assessed the relationship between COMT genotype and diagnosis and then tested for effects on cognition. We observed a modest but significant association between SNP rs165599 and BPD I, with the g allele being over-represented in cases versus controls (odds ratio, OR = 2.41; allelic p = 0.02; genotypic p = 0.04). Further, we found a relationship between the risk allele at this SNP and poorer performance on measures of verbal memory [California Verbal Learning Test (CVLT) Trials 1-5; p = 0.005, eta(2) = 0.07] particularly with regard to prefrontal aspects of learning (CVLT semantic cluster; p = 0.037, eta(2) = 0.04) in patients with BPD and in healthy controls. The common Val158Met polymorphism was not associated with diagnosis (p = 0.32) or cognition in our sample. These data suggest that COMT genetic variation at SNP rs165599 is associated with BPD I and influences prefrontal aspects of verbal memory in bipolar patients and healthy controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 235 | Schizophr Bull 2007 May 33: 635-41 |
| PMID | 17412710 |
| Title | Is COMT a susceptibility gene for schizophrenia? |
| Abstract | Catechol-O-methyl transferase (COMT) is a catabolic enzyme involved in the degradation of a number of bioactive molecules; of principal interest to psychiatry, these include dopamine. The enzyme is encoded by the COMT gene. COMT is located (along with 47 other genes) in a fragment of chromosome 22q11 which when deleted results in a complex syndrome, the psychiatric manifestations of which include schizophrenia and other psychoses. These 2 observations have placed COMT near the top of a rather long list of plausible candidate genes for schizophrenia. The ability to test the hypothesis that COMT might be a susceptibility gene for schizophrenia has been simplified in principle by the existence of a valine-to-methionine (Val/Met) polymorphism which results respectively in high and low activity forms of the enzyme. Given the unequivocal effect of this polymorphism on the function of COMT, and the evidence for a critical role for dopamine in the pathophysiology and treatment of psychosis, there are strong prior expectations that Val/Met influences susceptibility to schizophrenia as well as other psychiatric phenotypes. Indeed the Val/Met polymorphism has become the most widely studied polymorphism in psychiatry. In this review, we consider the evidence for and against the involvement of COMT in schizophrenia. The current data allow us to virtually exclude a simple relationship between schizophrenia and the Val/Met variant previously thought to dominate COMT function. However, recent data suggest a more complex pattern of genetic regulation of COMT function beyond that attributable to the Val/Met locus. Moreover, it is also clear that there is a complex nonlinear relationship between dopamine availability and brain function. These 2 factors, allied to phenotypic complexity within schizophrenia, make it difficult to draw strong conclusions regarding COMT in schizophrenia. Nevertheless, emerging research that takes greater account of all these levels of complexity is beginning to provide tantalizing, but far from definitive, support for the view that COMT influences susceptibility to at least some forms of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 236 | Am J Psychiatry 2007 Apr 164: 663-9 |
| PMID | 17403981 |
| Title | Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. |
| Abstract | The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The authors conducted a longitudinal evaluation of adolescents with 22q11.2 deletion syndrome to identify early risk factors for the development of psychotic disorders. Sixty children, 31 with 22q11.2 deletion syndrome and 29 comparison subjects with idiopathic developmental disability matched for age and IQ, underwent a baseline evaluation between 1998 and 2000; of these, 51 children (28 and 23 in the two groups, respectively) underwent follow-up evaluation between 2003 and 2005. A standardized comprehensive psychiatric, psychological, and adaptive functioning evaluation was conducted in both waves. Participants with 22q11.2 deletion syndrome were also genotyped for the catechol O-methyltransferase (COMT) Met/Val polymorphism and underwent magnetic resonance imaging scans. The two groups had similar baseline neuropsychiatric profiles. At follow-up, 32.1% of subjects with 22q11.2 deletion syndrome had developed psychotic disorders as compared with 4.3% of comparison subjects. In the 22q11.2 deletion syndrome group, baseline subthreshold psychotic symptoms interacted both with the COMT genotype and with baseline symptoms of anxiety or depression to predict 61% of the variance in severity of psychosis at follow-up evaluation. Lower baseline verbal IQ was also associated with more severe psychotic symptoms at follow-up evaluation. Genetic, cognitive, and psychiatric risk factors for the evolution of psychotic disorders in 22q11.2 deletion syndrome during adolescence were identified. Early intervention in the subgroup of children with subthreshold signs of psychosis and internalizing symptoms (especially anxiety symptoms) may reduce the risk of developing psychotic disorders during adolescence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 237 | Neurosci. Lett. 2007 May 417: 271-4 |
| PMID | 17383818 |
| Title | Influence of catechol-O-methyltransferase Val158Met polymorphism on neuropsychological and functional outcomes of classical rehabilitation and cognitive remediation in schizophrenia. |
| Abstract | Neurocognitive deficits are recognized as core features of schizophrenia and have a great impact on functional outcome. Recent reports have suggested that a functional polymorphism, Val158Met, of the catechol-O-methyltransferase (COMT) gene, partially influences cognitive performances (mainly cognitive flexibility and working memory) both in schizophrenic patients and in healthy controls, probably by modulating prefrontal dopamine function. While previous studies focused on single evaluation of cognitive functioning, we aimed to analyse the additive effect of COMT genotype and cognitive exercise on dynamic modulation of cognitive performances. We analysed the COMT Val158Met polymorphism in 50 patients with chronic schizophrenia randomly allocated to two treatment conditions for 3 months: standard rehabilitation treatment (SRT) alone and SRT plus specific cognitive exercise of impaired functions. We then divided our sample in four subgroups on the basis of genotype (Val/Val versus Met carriers) and treatment (placebo versus active). We assessed patients with a neuropsychological battery, the Positive and Negative Symptoms Scale (PANSS) and the Quality of Life Scale (QLS) at enrolment, after 3 months of therapy and after further 3 months of follow-up. We found significantly greater improvement of cognitive flexibility performance and QLS total score for Met carriers on active treatment in comparison to Val/Val on placebo. The findings support the hypothesis that COMT polymorphism influences individual capacity to recover from cognitive deficit through rehabilitation therapy after a wider intervention also including deficit-specific cognitive exercise as a potentiating tool. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 238 | Pharmacogenomics J. 2007 Dec 7: 418-26 |
| PMID | 17363961 |
| Title | Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. |
| Abstract | Genetic variation in the catechol-O-methyltransferase (COMT) gene may influence the susceptibility to schizophrenia and the response to neuroleptic treatment. The authors tested for an association between a COMT haplotype and schizophrenia-spectrum disorders and for an eventual influence of a specific COMT genotype in the clinical outcome and in the response to treatment. The genotypes for single nucleotide polymorphisms rs737865, rs4633, rs6267, rs4680 (Val 158 Met) and rs165599 were determined in 207 patients with schizophrenia-spectrum disorders and 204 paired controls. Statistical tests for linkage disequilibrium and for case-control differences in haplotype frequencies were performed using log-linear modelling embedded within the expectation-maximization algorithm. P-values based on permutations were calculated using the software UNPHASED, and odds ratios were estimated using the SHEsis platform. The response to neuroleptic treatment was assessed by the Global Assessment of Functioning scale and the severity of psychotic symptoms by the positive and negative syndrome scale (PANSS) scale. The overall disease status was significantly associated with the T-G (Val) diplotype for rs4633-rs4680 (P=0.0049). A significant association was observed between schizophrenia, but not other related disorders, and genotypes GG (Val/Val) for rs4680 and TT for rs4633. Val/Val patients with schizophrenia showed a higher severity of the psychotic symptoms and a worse response to the neuroleptic treatment. COMT genetic variation seems to be involved in the psychotic symptomatology of the schizophrenia-spectrum disorders and specifically in the narrow schizophrenia phenotype. Our results show an influence of the Val 158 Met polymorphism on the severity of psychotic symptoms and on the response to treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 239 | Med Clin (Barc) 2007 Jan 128: 41-4 |
| PMID | 17266899 |
| Title | [COMT Val158Met polymorphism and schizophrenia in a series of Spanish patients]. |
| Abstract | Catecol-O-methyl transferase (COMT) enzyme plays a significant role in the regulation of the dopaminergic system in the prefrontal cortex. Several studies have assessed the association between modifications of the COMT activity and schizophrenia, but without consistent results. COMT gene contains a single nucleotide functional polymorphism which produces the change of a valine for a methionine at position 158. The effect of this aminoacid change is a modification of COMT enzymatic activity: valine-COMT displays a significantly higher capacity of postsynaptic dopamine degradation than methionine-COMT. The objective of this study is to carry out a genetic association study of the functional polymorphism Val158Met in a sample of Spanish schizophrenic patients and healthy controls. This is a case-control study made up of 177 patients and 141 healthy controls. All patients -115 males and 62 females, with ages between 27 and 49 years; mean (standard deviation) of 38 (10.7) years- were being treated in the outpatient Psychiatric Clinic of the Hospital Universitario 12 de Octubre, and fulfilled the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria for schizophrenia (n = 162) or schizoaffective disorder (n = 15). Control subjects -92 males and 49 females, with ages between 26 and 47 years; mean of 36 (9.4) years- were free from medical and psychiatric disorders. Genotype identification was done by means of human genetic molecular techniques coupled to ADN polymerase chain reaction and single strand conformational polymorphism (SSCP) of the COMT Val158Met polymorphism. No statisticaly significant differences were found in the allele frequencies for this polymorphism between patient and control samples. Nevertheless, in genotype analysis and when a model of recessive inheritance (Val/Val vs Val/Met and Met/Met) was assumed, a possible tendency towards statistical significance was observed. Our results do not allow to confirm the possible COMT gene variants contribution to schizophrenia etiopathogenesis, but they offer some evidence which would point to its implication in some patients subgroups. With the results obtained in this study a possible contribution of the COMT gene in schizophrenia etiopathogenesis cannot be ruled out. The issue of the possible effect of the COMT Val158Met polymorphism in schizophrenia would remain to be open and calls for the need to replicate this kind of studies in greater samples that will allow stratificate analysis by patients subgroups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 240 | Biol. Psychiatry 2007 May 61: 1135-40 |
| PMID | 17217925 |
| Title | Catechol-O-methyl transferase and expression of schizophrenia in 73 adults with 22q11 deletion syndrome. |
| Abstract | Catechol-O-methyl transferase (COMT) is a candidate gene for schizophrenia with a role in dopamine metabolism, particularly in frontal cortex. COMT is within the region commonly deleted in 22q11 deletion syndrome (22q11DS), a syndrome with high prevalence of schizophrenia. We examined the role of COMT in schizophrenia-related expression in 22q11DS. We genotyped the COMT functional Val(158/108)Met allele in 73 Caucasian adults with 22q11DS (36 men, 37 women; aged 33.8, SD 10.1 years; 37 Met, 36 Val hemizygosity) blind to clinical data and assessed effects on symptoms and frontal functioning. The lower activity Met allele was not significantly more prevalent than the Val allele in 33 subjects with schizophrenia. Excitement symptoms were more severe, however, and three frontal cognitive tests (theory of mind, Trails B, and olfactory identification), communication, and social functioning measures showed significantly worse performance with Met allele hemizygosity, even after accounting for effects of schizophrenia. The results suggest that hemizygosity of the COMT functional allele exerts an effect on some measures of frontal functioning in 22q11DS. Elevated levels of tonic dopamine activation associated with the COMT Met allele may underlie these aspects of expression. We must look elsewhere for causes of the high prevalence of schizophrenia in 22q11DS, however. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 241 | Am J Psychiatry 2007 Jan 164: 142-9 |
| PMID | 17202556 |
| Title | Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children. |
| Abstract | The study aimed to determine the cognitive effect of the Val108/158Met polymorphism in the catechol-O-methyltransferase (COMT) gene in children before and during puberty. This polymorphism affects cognitive function in healthy adults and may contribute to risk for schizophrenia. COMT genotype was determined for 8,707 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), a geographically defined general population cohort of children born between April 1, 1991, and Dec. 31, 1992, in the southwest of England. Fourteen measures of cognitive function--including working memory, verbal and motor inhibition, attentional control, and IQ--were assessed at ages 8 and 10 years. Any pubertal development at age 9 years was reported by parents. Effects of COMT genotype on cognition and interactions with gender and puberty were assessed using general linear models. In boys, genotype significantly affected executive function and explained up to 10 points normal variation in verbal IQ. The effects on IQ were significantly greater in pubertal than in prepubertal boys. In girls, there were no significant effects of genotype on cognition. This common polymorphism may be one of the genes of small effect that contribute to normal variation in IQ. The gender-specific nature of the effect and its possible interaction with puberty may be relevant to both normal cognitive and brain development and to abnormal development in disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 242 | Schizophr. Res. 2007 Feb 90: 86-96 |
| PMID | 17123785 |
| Title | COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. |
| Abstract | Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol-O-methyltransferase (COMT), a key enzyme involved in regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs). Specifically, several studies have identified an association between working memory and executive functions, and COMT val108/158met genotype in schizophrenia; although there have been several negative findings that are likely related to small sample sizes and, possibly, medication status of patients at the time of testing. The association between COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine was investigated in a relatively large prospective sample of patients with schizophrenia, most of whom were unmedicated at baseline. Patients were genotyped for the COMT val108/158met SNP after completing a cognitive battery consisting of tests of attention, working memory, verbal learning and memory, executive function, and verbal fluency at baseline and after 6 weeks and 6 months of treatment with clozapine. Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and val/met heterozygous patients demonstrated significantly greater improvement than val homozygous patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype, cognition, and cognitive improvement with atypical APDs in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 243 | Biol. Psychiatry 2007 Apr 61: 845-53 |
| PMID | 17123481 |
| Title | Effect of schizotypy on cognitive performance and its tuning by COMT val158 met genotype variations in a large population of young men. |
| Abstract | Mirroring schizophrenia, specific dimensions of schizotypy are related to cognitive dysfunction. The relation of schizotypy and state psychopathology to cognitive performance and its link to catechol-O-methyltransferase (COMT) val(158) met genotype variations was studied in a large sample of young men. State psychopathology and schizotypy were assessed with self-rated questionnaires. Cognitive performance was assessed with tests of reasoning ability, sustained attention, and verbal and spatial working memory. Subjects were genotyped for the val(158) met polymorphism of the gene for COMT (low enzymatic activity met/met, intermediate met/val, and high val/val). The val/val group had higher scores in measures of state psychopathology as well as negative and disorganized schizotypy dimensions, whereas there was no effect of COMT genotype on cognitive performance measures. Structural equation modeling showed that cognitive performance accuracy but not speed decreased with increasing negative schizotypy, increased with increasing paranoid schizotypy, and was not affected by state psychopathology. Increasing val loading resulted in a dose-dependent increase in the factor loading for the relation between negative schizotypy and cognitive performance accuracy. Different schizotypal phenotypes had opposing relations to cognitive performance in the population. COMT genotype modulated the relation between the negative schizotypal phenotype and cognitive performance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 244 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 64-8 |
| PMID | 17034018 |
| Title | Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele. |
| Abstract | Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the schizotypal Personality Questionnaire (SPQ). We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 245 | Hum. Genet. 2007 Feb 120: 837-45 |
| PMID | 17028864 |
| Title | Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome. |
| Abstract | 22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 246 | Biol. Psychiatry 2007 May 61: 1127-34 |
| PMID | 17014827 |
| Title | Relationship of catechol-O-methyltransferase variants to brain structure and function in a population at high risk of psychosis. |
| Abstract | There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons. In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known. The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance. The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 247 | Hum. Genet. 2007 Feb 120: 889-906 |
| PMID | 17006672 |
| Title | Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 248 | Neuropsychopharmacology 2007 Jan 32: 162-70 |
| PMID | 16823382 |
| Title | Impact of catechol-O-methyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders. |
| Abstract | The enzyme catechol-O-methyltransferase (COMT) has attracted increasing interest regarding a genetic disposition towards schizophrenias and as a modulator of prefrontal brain function. A common SNP in the COMT gene causes a Val to Met transition at AA158/AA108 (Val158Met), resulting in reduced COMT activity in Met allele carriers. An impact of COMT genotype on cognition has been well established; however, the exact nature of this influence has yet to be elucidated. The aim of this study was to determine whether COMT genotype affects an electrophysiological marker of prefrontal activation and neuropsychological frontal lobe measures in schizophrenia. To this end, 56 acutely psychotic in-patients with schizophrenia spectrum disorders were investigated. Patients with the COMT 1947AA (Met/Met) genotype (n=13) were compared to a carefully matched sample of patients with a G1947A (Val/Met) genotype (n=15); matching criteria included patients' age, handedness, gender distribution, diagnosis, and medication status. A small group of six homozygous Val allele carriers was additionally included to allow an assessment of possible gene-dosage effects. P300 amplitudes and latencies, as well as an electrophysiological marker of prefrontal brain function (NoGo-Anteriorization/NGA) and neuropsychological measures (Stroop Test, Verbal Fluency, Trail Making Test) were regarded. Homozygous Met allele carriers had significantly increased NGA values and fronto-central Nogo amplitudes compared to patients with at least one Val allele. They also tended to perform better in the Stroop task, as compared to the matched group of Val/Met patients. These results indicate that COMT genotype exerts a strong impact on prefrontal functioning and executive control in schizophrenia spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 249 | Neurosci Biobehav Rev 2007 -1 31: 60-78 |
| PMID | 16782199 |
| Title | Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. |
| Abstract | A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 250 | Cereb. Cortex 2007 May 17: 1007-19 |
| PMID | 16751296 |
| Title | DRD4 and DAT1 polymorphisms modulate human gamma band responses. |
| Abstract | Gamma oscillations (30-80 Hz) have been demonstrated to be important for perceptual and cognitive processes. Animal and in vitro studies have revealed possible underlying generation mechanisms of the gamma rhythm. However, little is known about the neurochemical modulation of these oscillations during human cognition. schizophrenia and Attention Deficit Hyperactivity Disorder, which lead to failure of attentional modulation and working memory, introduce significant changes in gamma responses and have significant associations with genetic polymorphisms of dopamine receptor D4 (DRD4), dopamine transporter (DAT), and catechol-O-methyltransferase (COMT). Therefore, the presence of direct relations between these polymorphisms and gamma oscillations was investigated in human subjects using an auditory target detection paradigm. The 7-repeat isoform of the DRD4 polymorphism that produces a subsensitive variant of the D4 receptor enhanced the auditory evoked and induced gamma responses to both standard and target stimuli. The 10/10 genotype of the DAT1 polymorphism, which reduces DAT expression and hence yields an increase in extracellular dopamine, specifically enhanced evoked gamma responses to target stimuli. The COMT polymorphism did not significantly change gamma responses. It seems plausible to assume that the modulation pattern of the evoked gamma response by DRD4 polymorphism relates to reduced inhibition via the D4 receptor, whereas the DAT1 effect is related to the target detection mechanism probably mediated by the D1 receptor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 251 | Int. J. Neuropsychopharmacol. 2007 Jun 10: 301-8 |
| PMID | 16734939 |
| Title | Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome. |
| Abstract | Velocardiofacial syndrome (VCFS) is caused by a microdeletion in chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. The catechol-O-methyltransferase (COMT), residing in the 22q11.2 microdeletion region, is a major candidate gene for genetic susceptibility to neuropsychiatric disorders in VCFS. Individuals with VCFS carrying the low-activity allele (COMTL) are expected to have the lowest possible COMT activity since they have only a single copy of the gene. We explored the possibility that COMTL is associated with psychiatric disorders commonly found in VCFS. Fifty-five unrelated individuals with VCFS underwent psychiatric evaluation and were genotyped for the COMT 158Val/Met polymorphism coding for COMT high/low-activity alleles. The COMTL allele was significantly more prevalent in VCFS subjects with attention deficit hyperactivity disorder (ADHD) (73.9% vs. 33.3%, OR 5.67, chi2=7.76, p=0.005) and obsessive-compulsive disorder (OCD) (78.6% vs. 33.3%, OR 7.33, chi2=7.24, p=0.007) than in the control group (VCFS subjects without OCD, ADHD and schizophrenia/schizoaffective (SZ/SZaff) disorder). The results of this study suggest that greatly reduced COMT activity, as expected in VCFS COMTL individuals may be a risk factor for psychiatric sequelae in this population. Future longitudinal studies focusing on additional COMT polymorphic sites and other candidate genes from the deleted region will elucidate the molecular pathways leading to schizophrenia and other psychiatric disorders in VCFS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 252 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 253 | Mol. Psychiatry 2007 Sep 12: 854-69 |
| PMID | 17767149 |
| Title | Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. |
| Abstract | Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD(67)), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5' flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5' untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 254 | Neurosci. Lett. 2007 May 417: 271-4 |
| PMID | 17383818 |
| Title | Influence of catechol-O-methyltransferase Val158Met polymorphism on neuropsychological and functional outcomes of classical rehabilitation and cognitive remediation in schizophrenia. |
| Abstract | Neurocognitive deficits are recognized as core features of schizophrenia and have a great impact on functional outcome. Recent reports have suggested that a functional polymorphism, Val158Met, of the catechol-O-methyltransferase (COMT) gene, partially influences cognitive performances (mainly cognitive flexibility and working memory) both in schizophrenic patients and in healthy controls, probably by modulating prefrontal dopamine function. While previous studies focused on single evaluation of cognitive functioning, we aimed to analyse the additive effect of COMT genotype and cognitive exercise on dynamic modulation of cognitive performances. We analysed the COMT Val158Met polymorphism in 50 patients with chronic schizophrenia randomly allocated to two treatment conditions for 3 months: standard rehabilitation treatment (SRT) alone and SRT plus specific cognitive exercise of impaired functions. We then divided our sample in four subgroups on the basis of genotype (Val/Val versus Met carriers) and treatment (placebo versus active). We assessed patients with a neuropsychological battery, the Positive and Negative Symptoms Scale (PANSS) and the Quality of Life Scale (QLS) at enrolment, after 3 months of therapy and after further 3 months of follow-up. We found significantly greater improvement of cognitive flexibility performance and QLS total score for Met carriers on active treatment in comparison to Val/Val on placebo. The findings support the hypothesis that COMT polymorphism influences individual capacity to recover from cognitive deficit through rehabilitation therapy after a wider intervention also including deficit-specific cognitive exercise as a potentiating tool. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 255 | Med Clin (Barc) 2007 Jan 128: 41-4 |
| PMID | 17266899 |
| Title | [COMT Val158Met polymorphism and schizophrenia in a series of Spanish patients]. |
| Abstract | Catecol-O-methyl transferase (COMT) enzyme plays a significant role in the regulation of the dopaminergic system in the prefrontal cortex. Several studies have assessed the association between modifications of the COMT activity and schizophrenia, but without consistent results. COMT gene contains a single nucleotide functional polymorphism which produces the change of a valine for a methionine at position 158. The effect of this aminoacid change is a modification of COMT enzymatic activity: valine-COMT displays a significantly higher capacity of postsynaptic dopamine degradation than methionine-COMT. The objective of this study is to carry out a genetic association study of the functional polymorphism Val158Met in a sample of Spanish schizophrenic patients and healthy controls. This is a case-control study made up of 177 patients and 141 healthy controls. All patients -115 males and 62 females, with ages between 27 and 49 years; mean (standard deviation) of 38 (10.7) years- were being treated in the outpatient Psychiatric Clinic of the Hospital Universitario 12 de Octubre, and fulfilled the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria for schizophrenia (n = 162) or schizoaffective disorder (n = 15). Control subjects -92 males and 49 females, with ages between 26 and 47 years; mean of 36 (9.4) years- were free from medical and psychiatric disorders. Genotype identification was done by means of human genetic molecular techniques coupled to ADN polymerase chain reaction and single strand conformational polymorphism (SSCP) of the COMT Val158Met polymorphism. No statisticaly significant differences were found in the allele frequencies for this polymorphism between patient and control samples. Nevertheless, in genotype analysis and when a model of recessive inheritance (Val/Val vs Val/Met and Met/Met) was assumed, a possible tendency towards statistical significance was observed. Our results do not allow to confirm the possible COMT gene variants contribution to schizophrenia etiopathogenesis, but they offer some evidence which would point to its implication in some patients subgroups. With the results obtained in this study a possible contribution of the COMT gene in schizophrenia etiopathogenesis cannot be ruled out. The issue of the possible effect of the COMT Val158Met polymorphism in schizophrenia would remain to be open and calls for the need to replicate this kind of studies in greater samples that will allow stratificate analysis by patients subgroups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 256 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 64-8 |
| PMID | 17034018 |
| Title | Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele. |
| Abstract | Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the schizotypal Personality Questionnaire (SPQ). We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 257 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 258 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 259 | Biol. Psychiatry 2007 Apr 61: 845-53 |
| PMID | 17123481 |
| Title | Effect of schizotypy on cognitive performance and its tuning by COMT val158 met genotype variations in a large population of young men. |
| Abstract | Mirroring schizophrenia, specific dimensions of schizotypy are related to cognitive dysfunction. The relation of schizotypy and state psychopathology to cognitive performance and its link to catechol-O-methyltransferase (COMT) val(158) met genotype variations was studied in a large sample of young men. State psychopathology and schizotypy were assessed with self-rated questionnaires. Cognitive performance was assessed with tests of reasoning ability, sustained attention, and verbal and spatial working memory. Subjects were genotyped for the val(158) met polymorphism of the gene for COMT (low enzymatic activity met/met, intermediate met/val, and high val/val). The val/val group had higher scores in measures of state psychopathology as well as negative and disorganized schizotypy dimensions, whereas there was no effect of COMT genotype on cognitive performance measures. Structural equation modeling showed that cognitive performance accuracy but not speed decreased with increasing negative schizotypy, increased with increasing paranoid schizotypy, and was not affected by state psychopathology. Increasing val loading resulted in a dose-dependent increase in the factor loading for the relation between negative schizotypy and cognitive performance accuracy. Different schizotypal phenotypes had opposing relations to cognitive performance in the population. COMT genotype modulated the relation between the negative schizotypal phenotype and cognitive performance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 260 | Biol. Psychiatry 2007 Apr 61: 845-53 |
| PMID | 17123481 |
| Title | Effect of schizotypy on cognitive performance and its tuning by COMT val158 met genotype variations in a large population of young men. |
| Abstract | Mirroring schizophrenia, specific dimensions of schizotypy are related to cognitive dysfunction. The relation of schizotypy and state psychopathology to cognitive performance and its link to catechol-O-methyltransferase (COMT) val(158) met genotype variations was studied in a large sample of young men. State psychopathology and schizotypy were assessed with self-rated questionnaires. Cognitive performance was assessed with tests of reasoning ability, sustained attention, and verbal and spatial working memory. Subjects were genotyped for the val(158) met polymorphism of the gene for COMT (low enzymatic activity met/met, intermediate met/val, and high val/val). The val/val group had higher scores in measures of state psychopathology as well as negative and disorganized schizotypy dimensions, whereas there was no effect of COMT genotype on cognitive performance measures. Structural equation modeling showed that cognitive performance accuracy but not speed decreased with increasing negative schizotypy, increased with increasing paranoid schizotypy, and was not affected by state psychopathology. Increasing val loading resulted in a dose-dependent increase in the factor loading for the relation between negative schizotypy and cognitive performance accuracy. Different schizotypal phenotypes had opposing relations to cognitive performance in the population. COMT genotype modulated the relation between the negative schizotypal phenotype and cognitive performance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 261 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 64-8 |
| PMID | 17034018 |
| Title | Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele. |
| Abstract | Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the schizotypal Personality Questionnaire (SPQ). We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 262 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 64-8 |
| PMID | 17034018 |
| Title | Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele. |
| Abstract | Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the schizotypal Personality Questionnaire (SPQ). We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 263 | Neuropsychopharmacology 2007 Jan 32: 162-70 |
| PMID | 16823382 |
| Title | Impact of catechol-O-methyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders. |
| Abstract | The enzyme catechol-O-methyltransferase (COMT) has attracted increasing interest regarding a genetic disposition towards schizophrenias and as a modulator of prefrontal brain function. A common SNP in the COMT gene causes a Val to Met transition at AA158/AA108 (Val158Met), resulting in reduced COMT activity in Met allele carriers. An impact of COMT genotype on cognition has been well established; however, the exact nature of this influence has yet to be elucidated. The aim of this study was to determine whether COMT genotype affects an electrophysiological marker of prefrontal activation and neuropsychological frontal lobe measures in schizophrenia. To this end, 56 acutely psychotic in-patients with schizophrenia spectrum disorders were investigated. Patients with the COMT 1947AA (Met/Met) genotype (n=13) were compared to a carefully matched sample of patients with a G1947A (Val/Met) genotype (n=15); matching criteria included patients' age, handedness, gender distribution, diagnosis, and medication status. A small group of six homozygous Val allele carriers was additionally included to allow an assessment of possible gene-dosage effects. P300 amplitudes and latencies, as well as an electrophysiological marker of prefrontal brain function (NoGo-Anteriorization/NGA) and neuropsychological measures (Stroop Test, Verbal Fluency, Trail Making Test) were regarded. Homozygous Met allele carriers had significantly increased NGA values and fronto-central Nogo amplitudes compared to patients with at least one Val allele. They also tended to perform better in the Stroop task, as compared to the matched group of Val/Met patients. These results indicate that COMT genotype exerts a strong impact on prefrontal functioning and executive control in schizophrenia spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 264 | Neuropsychiatr Dis Treat 2007 Dec 3: 925-34 |
| PMID | 19300629 |
| Title | Catechol-O-methyltransferase Val158Met genotype in healthy and personality disorder individuals: Preliminary results from an examination of cognitive tests hypothetically differentially sensitive to dopamine functions. |
| Abstract | A functional polymorphism of the gene coding for Catechol-O-methyltrasferase (COMT), an enzyme responsible for the degradation of the catecholamine dopamine (DA), epinephrine, and norepinephrine, is associated with cognitive deficits. However, previous studies have not examined the effects of COMT on context processing, as measured by the AX-CPT, a task hypothesized to be maximally relevant to DA function. 32 individuals who were either healthy, with schizotypal personality disorder, or non-cluster A, personality disorder (OPD) were genotyped at the COMT Val158Met locus. Met/Met (n = 6), Val/Met (n = 10), Val/Val (n = 16) individuals were administered a neuropsychological battery, including the AX-CPT and the N-back working memory test. For the AX-CPT, Met/Met demonstrated more AY errors (reflecting good maintenance of context) than the other genotypes, who showed equivalent error rates. Val/Val demonstrated disproportionately greater deterioration with increased task difficulty from 0-back to 1-back working memory demands as compared to Met/Met, while Val/Met did not differ from either genotypes. No differences were found on processing speed or verbal working memory. Both context processing and working memory appear related to COMT genotype and the AX-CPT and N-back may be most sensitive to the effects of COMT variation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 265 | Mol. Psychiatry 2008 Sep 13: 873-7 |
| PMID | 18195713 |
| Title | Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. |
| Abstract | The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 266 | Schizophr. Res. 2008 Mar 100: 308-15 |
| PMID | 18164902 |
| Title | Analyses of variants located in estrogen metabolism genes (ESR1, ESR2, COMT and APOE) and schizophrenia. |
| Abstract | Relationships between gender, age-of-onset of schizophrenia and reproductive age strongly suggest a key role for gonadal hormones, and more specifically for estrogens, in the etiology of the illness. Also, estrogens act as neural growth and trophic factors influencing neuron and glial cells in many areas of the central nervous system. Therefore, we investigated the association between schizophrenia and 4 genes related to estrogen metabolism. These genes are ESR1 (estrogen receptor 1), ESR2 (estrogen receptor 2), APOE (apolipoprotein E) and COMT (catechol-O-methyltransferase). The expression of APOE and COMT, which contain estrogen response elements, have been demonstrated to be regulated by the estrogen receptors. In this current association study, we examined 59 single nucleotide polymorphisms (SNPs) located in the ESR1 (26), ESR2 (14), APOE (7) and COMT (12) loci. Allele frequencies were evaluated in the schizophrenia (n=585)-control (n=615) sample and no association was found with any of the four genes. In conclusion, our data suggest that the four analyzed genes do not play an important role in susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 267 | Neuroreport 2008 Jul 19: 1155-8 |
| PMID | 18596619 |
| Title | Effects of brain-derived neurotrophic factor-catecholamine-O-methyltransferase gene interaction on schizophrenic symptoms. |
| Abstract | The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O-methyltransferase (COMT L) is associated with a deficit in attention and aggravation of delusions in schizophrenia. We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited. The patients who were BDNF met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions. The current results suggest that patients with the BDNF met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 268 | Med Clin (Barc) 2008 Dec 131: 761-4 |
| PMID | 19094875 |
| Title | [Effect of polymorphisms of the cathecol-O-methyltransferase on schizophrenia risk in a Spanish population]. |
| Abstract | Cathecol-O-methyl transferase (COMT) is one of the most plausible susceptibility genes of schizophrenia risk. The main genetic variant (G158A or rs4680) studied is functional. It has been shown that G-A transition at COMT codon 158 makes COMT more thermolabile and less active at physiological temperature. Genetic variants in the P2 promoter have been suggested to cause alterations in brain COMT protein levels. A variant in the P2 promoter (-278A/G or rs1800706) has recently been associated with psychotic disorders. We studied whether polymorphisms in COMT (G158A, -278A/G) are risk factors for schizophrenia in a Spanish population. 243 subjects diagnosed of schizophrenia and related disorders following the DSM-IV criteria and 291 hospital-based controls participated in an association study. The heterozygotes for the COMT -278A/G polymorphism showed a 60% reduction in the schizophrenia risk (p = 0.009). No significant differences were observed between the other COMT genotypes or haplotypes in cases and controls. Our results suggest that the COMT -278A/G polymorphism may have a role in schizophrenia. The results are in agreement with recent findings in this field that indicate a minor influence of COMT G158A on schizophrenia risk and a greater importance of polymorphisms in the P2 promoter regions of COMT, such as -278A/G. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 269 | J Abnorm Psychol 2008 Nov 117: 788-98 |
| PMID | 19025226 |
| Title | Anhedonia as a phenotype for the Val158Met COMT polymorphism in relatives of patients with schizophrenia. |
| Abstract | The Val(158)Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with aspects of schizophrenia that are possibly related to the disorder's pathogenesis. The present study investigated the Val(158)Met polymorphism in relation to anhedonia--a construct central to negative schizotypy. Anhedonia and other schizotypal characteristics were assessed in relatives of patients with schizophrenia, relatives of patients with bipolar disorder, and nonpsychiatric controls using the Chapman schizotypy scales and the schizotypal Personality Questionnaire. Compared with controls, relatives of individuals with schizophrenia had elevated scores on Chapman scales for social anhedonia and physical anhedonia, while relatives of patients with bipolar disorder exhibited only increased scores on the Social Anhedonia Scale. As a group, relatives of patients with schizophrenia who were homozygous for the val allele of the COMT polymorphism showed the highest elevations in self-reported social and physical anhedonia. Associations with the COMT polymorphism were absent in relatives of patients with bipolar disorder and control participants. Findings suggest that anhedonia is manifest in individuals who carry genetic liability for schizophrenia and is associated with the Val(158)Met polymorphism of the COMT gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 270 | Proc. Natl. Acad. Sci. U.S.A. 2008 Sep 105: 14609-14 |
| PMID | 18794526 |
| Title | A catechol-O-methyltransferase that is essential for auditory function in mice and humans. |
| Abstract | We have identified a previously unannotated catechol-O-methyltranferase (COMT), here designated COMT2, through positional cloning of a chemically induced mutation responsible for a neurobehavioral phenotype. Mice homozygous for a missense mutation in COMT2 show vestibular impairment, profound sensorineuronal deafness, and progressive degeneration of the organ of Corti. Consistent with this phenotype, COMT2 is highly expressed in sensory hair cells of the inner ear. COMT2 enzymatic activity is significantly reduced by the missense mutation, suggesting that a defect in catecholamine catabolism underlies the auditory and vestibular phenotypes. Based on the studies in mice, we have screened DNA from human families and identified a nonsense mutation in the human ortholog of the murine COMT2 gene that causes nonsyndromic deafness. Defects in catecholamine modification by COMT have been previously implicated in the development of schizophrenia. Our studies identify a previously undescribed COMT gene and indicate an unexpected role for catecholamines in the function of auditory and vestibular sense organs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 271 | Eur Neuropsychopharmacol 2008 Nov 18: 820-5 |
| PMID | 18789857 |
| Title | Catechol-O-methyltransferase Val158Met polymorphism in relation to aggressive schizophrenia in a Korean population. |
| Abstract | We examined the association between the Catechol-O-methyltransferase (COMT) Val158Met polymorphism and aggressive schizophrenia. The sample included 61 aggressive schizophrenic patients as well as 104 non-aggressive patients from psychiatric hospitals and 415 healthy volunteers in South Korea. In the case-control comparisons, there was no significant association between the aggressive schizophrenic patients and the COMT Val158Met polymorphism. Looking only at the subgroup of aggressive schizophrenic patients, however, we found a dose-dependent relationship between the Met allele and verbal aggression. In this subgroup, the Met carriers showed a higher verbal aggression score than those with the Val/Val homozygote. These findings support the hypothesized moderating role of the COMT gene in the aggressive behaviour in some schizophrenic patients, though they do not support the existence of a direct association between the COMT Val158Met polymorphism and aggressive schizophrenia case status in the Korean population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 272 | Dev Disabil Res Rev 2008 -1 14: 26-34 |
| PMID | 18636634 |
| Title | Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome. |
| Abstract | There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk for the development of schizophrenia, with only a greater risk conferred by being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual. Both linkage and association studies of people with schizophrenia have implicated several susceptibility genes, of which three are in the 22q11.2 region; catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH), and Gnb1L. In addition, variation in Gnb1L is associated with the presence of psychosis in males with 22q11.2DS. In mouse models of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is associated with reduced prepulse inhibition, a schizophrenia endophenotype. The study of 22q11.2DS provides an attractive model to increase our understanding of the development and pathogenesis of schizophrenia and other psychiatric disorders in 22q11.2DS and in wider population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 273 | Schizophr. Res. 2008 Aug 103: 186-91 |
| PMID | 18571901 |
| Title | Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder. |
| Abstract | schizophrenia and bipolar disorder, although diagnostically separate, likely share elements of their genetic etiology. This study assessed whether the COMT Val158Met polymorphism has shared or specific associations with clinical phenotypes evident in schizophrenia and bipolar disorder. schizophrenia and bipolar patients completed a clinical assessment encompassing premorbid functioning and current and lifetime symptomatology. Multivariate analyses yielded a three-way interaction of diagnosis, COMT genotype for lifetime symptomatology. The COMT Val allele was associated with greater positive symptomatology in schizophrenia, whereas Met homozygosity was associated with greater positive symptomatology in bipolar disorder. Findings support the COMT Val158Met polymorphism conferring vulnerability for different clinical phenotypes in schizophrenia and bipolar disorder. Lifetime symptomatology may be particularly useful in determining the relationship between genes and clinical phenotypes across mental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 274 | Curr Psychiatry Rep 2008 Apr 10: 148-57 |
| PMID | 18474208 |
| Title | Schizophrenia and 22q11.2 deletion syndrome. |
| Abstract | 22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDS-schizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 275 | Neuropsychobiology 2008 -1 57: 22-5 |
| PMID | 18424907 |
| Title | Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene is not associated with tardive dyskinesia in schizophrenia. |
| Abstract | This study investigated whether the catechol-O-methyltransferase (COMT) gene V158M single-nucleotide polymorphism (SNP) influences susceptibility to tardive dyskinesia (TD). We examined 209 Korean schizophrenic patients using the Abnormal Involuntary Movement Scale (AIMS), with genotyping performed for the COMT gene V158M SNP. The logistic regression analysis showed that old age [p = 0.032, OR = 1.40 (OR corresponds to 10-year), 95% CI = 1.03-1.90] was a risk factor for TD, but there was no significant association between the COMT genotype and TD. The heterozygotes (MV genotype) of the COMT gene polymorphism tended to develop TD less than homozygotes (MM and VV); however, the risk did not reach statistical significance (p = 0.050, OR = 1.81, 95% CI = 1.00-3.29). These results suggest that the V158M SNP of the COMT gene is not associated with TD in schizophrenia. However, there is a tendency that the heterozygous genotype of the COMT gene polymorphism has a protective effect against TD. Further investigations are warranted to evaluate a molecular heterosis of this polymorphism in development of TD in a large sample of subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 276 | Schizophr. Res. 2008 Jul 102: 206-9 |
| PMID | 18407467 |
| Title | Lack of influence of COMT Val158Met genotype on cognition in first-episode non-affective psychosis. |
| Abstract | COMT gene is a logical candidate gene for schizophrenia. Moreover, variations in the COMT Val158Met functional polymorphism have been associated with prefrontal cognitive abnormalities among patients with schizophrenia, healthy relatives and controls. In this study, using an epidemiologically-based sample of 130 patients experiencing a first-episode of a non-affective psychosis, we examined whether COMT Val158Met genotype influenced cognitive performance on the phenotypic expression of psychosis. We found no significant differences in any cognitive measure according to COMT genotype. These findings, together with previously published research, put the relationship between COMT genotype and cognitive performance in doubt. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 277 | Mol. Psychiatry 2008 Aug 13: 821-7 |
| PMID | 18317466 |
| Title | COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET. |
| Abstract | A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 278 | Psychol Med 2008 Nov 38: 1651-8 |
| PMID | 18261249 |
| Title | Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism. |
| Abstract | Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC). PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 279 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 654-7 |
| PMID | 18163391 |
| Title | PRODH gene is associated with executive function in schizophrenic families. |
| Abstract | The aim of this study was to investigate the relationship between polymorphisms in the PRODH and COMT genes and selected neurocognitive functions. Six SNPs in PRODH and two SNPs in COMT were genotyped in 167 first-episode schizophrenic families who had been assessed by a set of 14 neuropsychological tests. Neuropsychological measures were selected as quantitative traits for association analysis. The haplotype of SNPs PRODH 1945T/C and PRODH 1852G/A was associated with impaired performance on the Tower of Hanoi, a problem-solving task mainly reflecting planning capacity. There was no significant evidence for association with any other neuropsychological traits for other SNPs or haplotypes of paired SNPs in the two genes. This study takes previous findings of association between PRODH and schizophrenia further by associating variation within the gene with performance on a neurocognitive trait characteristic of the illness. It fails to confirm previous reports of an association between COMT and cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 280 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 658-60 |
| PMID | 18163386 |
| Title | New functional single nucleotide polymorphism (Ala72Ser) in the COMT gene is associated with aggressive behavior in male schizophrenia. |
| Abstract | A new functional single nucleotide polymorphism (SNP) Ala72Ser in the COMT gene was discovered recently. The purpose of our study is to examine the association between Ala72Ser and Val158Met functional polymorphisms in COMT gene and homicidal behavior in schizophrenia. DNA was genotyped for the Ala72Ser and Val158Met SNPs of the COMT gene in a sample of 93 schizophrenic patients who committed homicide (H-SCZ) and 100 schizophrenic patients who had never committed homicide (NH-SCZ). A statistically significant difference was found in genotype distribution and allele frequencies in SNP Ala72Ser of COMT gene between H-SCZ and NH-SCZ group. In haplotype analysis, the frequency of the combination of high-high activity allele (Ala-Val) was lower in H-SCZ group than in NH-SCZ group (P = 0.000069). Our study showed a highly significant association between a COMT haplotype of two functional SNPs and aggressive behavior in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 281 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 550-6 |
| PMID | 18092319 |
| Title | Catechol-O-methyltransferase Val158Met polymorphism and clinical characteristics in first episode non-affective psychosis. |
| Abstract | Catechol-O-methyltransferase (COMT) Val158Met polymorphism has been identified as a potential etiologic factor in schizophrenia. It has been proposed that this polymorphism could be associated with specific clinical markers. The aim of the study was to evaluate the influence of COMT Val158Met polymorphism genotype in the phenotypic expression of first episode psychosis at onset. Age of onset, DUP, SANS, and SAPS (positive, disorganized, and negative dimensions) were studied in 169 Caucasian drug-naïve patients with a first-episode of non-affective psychosis. The COMT Val158Met polymorphism was typed using PCR amplification of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with COMT and gender as independent variables. Patients with Val/Val genotype had significantly higher levels of SANS negative dimension scores (F: 3.539; P = 0.031) and had a younger age of onset (F: 4.649; P = 0.011) than Met carriers. Our findings suggest that the Val allele is associated with onset phenotypic features related to a poor prognosis of the illness. These data would indicate that COMT genotype may have a role in the etiological model for schizophrenia and other psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 282 | Psychiatry Res 2008 Jan 157: 1-8 |
| PMID | 17850881 |
| Title | Catechol-O-methyltransferase gene and obsessive-compulsive symptoms in patients with recent-onset schizophrenia: preliminary results. |
| Abstract | The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia because of its role in the breakdown of dopamine in the prefrontal cortex. The COMT gene contains a functional polymorphism changing enzyme activity that has been associated with some neuropsychiatric (endo)phenotypes, e.g. cognitive performance and anxiety. In this study we investigated the association between the COMT Val(158)Met polymorphism and obsessive-compulsive symptoms in patients with schizophrenia. Severity of obsessive-compulsive symptoms in 77 male patients with recent-onset schizophrenia was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and the COMT Val(158)Met polymorphism was genotyped for these patients. We found a significant effect of the COMT genotype on Y-BOCS scores: the Val/Val genotype was associated with the highest Y-BOCS scores, whereas patients with the Met/Met genotype had the lowest Y-BOCS scores. Our data suggest that the COMT high-activity Val allele is associated with more obsessive-compulsive symptoms in young patients with schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism may be a modifier gene for the symptomatology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 283 | Eur Neuropsychopharmacol 2008 Feb 18: 99-106 |
| PMID | 17716874 |
| Title | Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia. |
| Abstract | Evidence is emerging for the association of aberrant homocysteine-methylation cycle and increased risk of schizophrenia. We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in 252 patients with schizophrenia and 405 control subjects. All subjects were of Dutch ancestry. The COMT 324AA genotype was not associated with an increased risk of schizophrenia (odds ratio (OR)=1.38 [95% CI: 0.88-2.16], P=0.162), and the MTHFR 677TT genotype showed a nearly significant increased risk for schizophrenia (OR=1.65 [95% CI: 0.97-2.82], P=0.067). The odds ratio for schizophrenia associated with joint occurrence of the COMT 324AA and MTHFR 677TT genotype was 3.08 (95% CI: 1.08-8.76) (P=0.035). Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia (test for trend, P=0.017). Our findings do not support a major role for the COMT 324AA and MTHFR 677TT genotype alone, but the combination of both genotypes might increase schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 284 | J. Clin. Invest. 2008 Jun 118: 2200-8 |
| PMID | 18497887 |
| Title | Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. |
| Abstract | AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 285 | Biol. Psychiatry 2008 Sep 64: 438-42 |
| PMID | 18466879 |
| Title | Association of a nonsynonymous variant of DAOA with visuospatial ability in a bipolar family sample. |
| Abstract | Bipolar disorder and schizophrenia are hypothesized to share some genetic background. In a two-phase study, we evaluated the effect of five promising candidate genes for psychotic disorders, DAOA, COMT, DTNBP1, NRG1, and AKT1, on bipolar spectrum disorder, psychotic disorder, and related cognitive endophenotypes in a Finnish family-based sample ascertained for bipolar disorder. In initial screening of 362 individuals from 63 families, we found only marginal evidence for association with the diagnosis-based dichotomous classification. Those associations did not strengthen when we genotyped the complete sample of 723 individuals from 180 families. We observed a significant association of DAOA variants rs3916966 and rs2391191 with visuospatial ability (Quantitative Transmission Disequilibrium Test [QTDT]; p = 4 x 10(-6) and 5 x 10(-6), respectively) (n = 159) with the two variants in almost complete linkage disequilibrium. The COMT variant rs165599 also associated with visuospatial ability, and in our dataset, we saw an additive effect of DAOA and COMT variants on this neuropsychological trait. The ancestral allele (Arg) of the nonsynonymous common DAOA variant rs2391191 (Arg30Lys) was found to predispose to impaired performance. The DAOA gene may play a role in predisposing individuals to a mixed phenotype of psychosis and mania and to impairments in related neuropsychological traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 286 | Am J Psychiatry 2008 Apr 165: 497-506 |
| PMID | 18198266 |
| Title | No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. |
| Abstract | The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 287 | Nat. Genet. 2008 Jul 40: 827-34 |
| PMID | 18583979 |
| Title | Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. |
| Abstract | In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 288 | Methods Mol. Biol. 2008 -1 448: 187-212 |
| PMID | 18370235 |
| Title | Epigenetic alterations of the dopaminergic system in major psychiatric disorders. |
| Abstract | Although there is evidence to link schizophrenia (SCZ) and bipolar disorder (BD) to genetic and environmental factors, specific individual or groups of genes/factors causative of the disease have been elusive to the research community. An understanding of the molecular aberrations that cause these mental illnesses requires comprehensive approaches that examine both genetic and epigenetic factors. Because of the overwhelming evidence for the role of environmental factors in the disease presentation, our initial approach involved deciphering how epigenetic changes resulting from promoter DNA methylation affect gene expression in SCZ and BD. Apparently, the central reversible but covalent epigenetic modification to DNA is derived from methylation of the cytosine residues that is potentially heritable and can affect gene expression and downstream activities. Environmental factors can influence DNA methylation patterns and hence alter gene expression. Such changes can be especially problematic in individuals with genetic susceptibilities to specific diseases. Recent reports from our laboratory provided compelling evidence that both hyper- and hypo-DNA methylation changes of the regulatory regions play critical roles in defining the altered functionality of genes in major psychiatric disorders such as SCZ and BD. In this chapter, we outline the technical details of the methods that could help to expand this line of research to assist with compiling the differential methylation-mediated epigenetic alterations that are responsible for the pathogenesis of SCZ, BD, and other mental diseases. We use the genes of the extended dopaminergic (DAergic) system such as membrane-bound catechol-O-methyltransferase (MB-COMT), monoamine oxidase A (MAOA), dopamine transporter 1 (DAT1), tyrosine hydroxylase (TH), dopamine (DA) receptors1 and 2 (DRD1/2), and related genes (e.g., reelin [RELN] and brain-derived neurotrophic factor [BDNF]) to illustrate the associations between differential promoter DNA methylations and disease phenotype. It is our hope that comprehensive analyses of the DAergic system as the prototype could provide the impetus and molecular basis to uncover early markers for diagnosis, help in the understanding of differences in disease severity in individuals with similar or identical genetic makeup, and assist with the identification of novel targets for therapeutic applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 289 | Curr Opin Psychiatry 2008 Mar 21: 161-7 |
| PMID | 18332664 |
| Title | Genes and structural brain imaging in schizophrenia. |
| Abstract | schizophrenia is a complex genetic disorder, caused by multiple genetic and environmental factors. Recently, studies have focused on testing specific genetic markers in a known candidate gene for association with endophenotypes. These are measurable characteristics of a disorder that are assumed to be closer to the action of the gene, resulting in higher genetic signal-to-noise ratios. Structural brain parameters have been shown to be useful endophenotypes for studies in psychiatric illnesses. After reviewing the available studies on the influence of genotype on brain volume in schizophrenia, it is evident that the BDNF and COMT genes are clearly favourites for genetic imaging studies. Results from these studies seem to be quite consistent, with the same associated alleles and direction of brain volume changes. The most frequently investigated polymorphisms suggest that sample sizes of approximately 50-100 patients are sufficient to report consistent findings. Considering the ongoing discussion about the sample size necessary to detect significant associations, however, larger sample sizes are needed. There is sufficient evidence to defend the use of structural neuroimaging as an endophenotype to investigate a complex phenotype such as schizophrenia despite the notion that, so far, no single causal pathway emerges from these studies. Replication studies and larger numbers of patients are essential in this respect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 290 | Neuroreport 2008 Jul 19: 1155-8 |
| PMID | 18596619 |
| Title | Effects of brain-derived neurotrophic factor-catecholamine-O-methyltransferase gene interaction on schizophrenic symptoms. |
| Abstract | The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O-methyltransferase (COMT L) is associated with a deficit in attention and aggravation of delusions in schizophrenia. We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited. The patients who were BDNF met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions. The current results suggest that patients with the BDNF met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 291 | Eur Neuropsychopharmacol 2008 Nov 18: 820-5 |
| PMID | 18789857 |
| Title | Catechol-O-methyltransferase Val158Met polymorphism in relation to aggressive schizophrenia in a Korean population. |
| Abstract | We examined the association between the Catechol-O-methyltransferase (COMT) Val158Met polymorphism and aggressive schizophrenia. The sample included 61 aggressive schizophrenic patients as well as 104 non-aggressive patients from psychiatric hospitals and 415 healthy volunteers in South Korea. In the case-control comparisons, there was no significant association between the aggressive schizophrenic patients and the COMT Val158Met polymorphism. Looking only at the subgroup of aggressive schizophrenic patients, however, we found a dose-dependent relationship between the Met allele and verbal aggression. In this subgroup, the Met carriers showed a higher verbal aggression score than those with the Val/Val homozygote. These findings support the hypothesized moderating role of the COMT gene in the aggressive behaviour in some schizophrenic patients, though they do not support the existence of a direct association between the COMT Val158Met polymorphism and aggressive schizophrenia case status in the Korean population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 292 | Neuropsychobiology 2008 -1 57: 22-5 |
| PMID | 18424907 |
| Title | Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene is not associated with tardive dyskinesia in schizophrenia. |
| Abstract | This study investigated whether the catechol-O-methyltransferase (COMT) gene V158M single-nucleotide polymorphism (SNP) influences susceptibility to tardive dyskinesia (TD). We examined 209 Korean schizophrenic patients using the Abnormal Involuntary Movement Scale (AIMS), with genotyping performed for the COMT gene V158M SNP. The logistic regression analysis showed that old age [p = 0.032, OR = 1.40 (OR corresponds to 10-year), 95% CI = 1.03-1.90] was a risk factor for TD, but there was no significant association between the COMT genotype and TD. The heterozygotes (MV genotype) of the COMT gene polymorphism tended to develop TD less than homozygotes (MM and VV); however, the risk did not reach statistical significance (p = 0.050, OR = 1.81, 95% CI = 1.00-3.29). These results suggest that the V158M SNP of the COMT gene is not associated with TD in schizophrenia. However, there is a tendency that the heterozygous genotype of the COMT gene polymorphism has a protective effect against TD. Further investigations are warranted to evaluate a molecular heterosis of this polymorphism in development of TD in a large sample of subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 293 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 654-7 |
| PMID | 18163391 |
| Title | PRODH gene is associated with executive function in schizophrenic families. |
| Abstract | The aim of this study was to investigate the relationship between polymorphisms in the PRODH and COMT genes and selected neurocognitive functions. Six SNPs in PRODH and two SNPs in COMT were genotyped in 167 first-episode schizophrenic families who had been assessed by a set of 14 neuropsychological tests. Neuropsychological measures were selected as quantitative traits for association analysis. The haplotype of SNPs PRODH 1945T/C and PRODH 1852G/A was associated with impaired performance on the Tower of Hanoi, a problem-solving task mainly reflecting planning capacity. There was no significant evidence for association with any other neuropsychological traits for other SNPs or haplotypes of paired SNPs in the two genes. This study takes previous findings of association between PRODH and schizophrenia further by associating variation within the gene with performance on a neurocognitive trait characteristic of the illness. It fails to confirm previous reports of an association between COMT and cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 294 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 658-60 |
| PMID | 18163386 |
| Title | New functional single nucleotide polymorphism (Ala72Ser) in the COMT gene is associated with aggressive behavior in male schizophrenia. |
| Abstract | A new functional single nucleotide polymorphism (SNP) Ala72Ser in the COMT gene was discovered recently. The purpose of our study is to examine the association between Ala72Ser and Val158Met functional polymorphisms in COMT gene and homicidal behavior in schizophrenia. DNA was genotyped for the Ala72Ser and Val158Met SNPs of the COMT gene in a sample of 93 schizophrenic patients who committed homicide (H-SCZ) and 100 schizophrenic patients who had never committed homicide (NH-SCZ). A statistically significant difference was found in genotype distribution and allele frequencies in SNP Ala72Ser of COMT gene between H-SCZ and NH-SCZ group. In haplotype analysis, the frequency of the combination of high-high activity allele (Ala-Val) was lower in H-SCZ group than in NH-SCZ group (P = 0.000069). Our study showed a highly significant association between a COMT haplotype of two functional SNPs and aggressive behavior in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 295 | Proc. Natl. Acad. Sci. U.S.A. 2008 Nov 105: 17573-8 |
| PMID | 18988738 |
| Title | MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met. |
| Abstract | Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val --> Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val --> Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C --> T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 296 | Pharmacopsychiatry 2008 Sep 41 Suppl 1: S89-98 |
| PMID | 18756426 |
| Title | A mathematical model of presynaptic dopamine homeostasis: implications for schizophrenia. |
| Abstract | Several lines of evidence implicate altered dopamine neurotransmission in schizophrenia. Current drugs for schizophrenia focus on postsynaptic sites of the dopamine signaling pathways, but do not target presynaptic dopamine metabolism. We have begun to develop a mathematical model of dopamine homeostasis, which will aid our understanding of how genetic, environmental, and pharmacological factors alter the functioning of the presynaptic dopamine neuron. Formulated within the modeling framework of BIOCHEMICAL SYSTEMS THEORY, the mathematical model integrates relevant metabolites, enzymes, transporters, and regulators involved in the control of the biochemical environment within the dopamine neuron. In this report we use the model to assess several components and factors that affect the dopamine neuron and have been implicated in schizophrenia. These include the enzymes COMT, MAO, and TH, different dopamine transporters, as well as administration of amphetamine or cocaine. We also investigate scenarios that could increase (or decrease) dopamine neurotransmission and thus exacerbate (or alleviate) symptoms of schizophrenia. Our results indicate that the model predicts the effects of various factors related to schizophrenia on the homeostasis of the presynaptic dopamine neuron rather well. Upon further refinements and testing, the model has the potential of serving as a tool for screening novel therapeutics aimed at altering presynaptic dopamine function and thereby potentially ameliorating some of the symptomology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 297 | Psychiatry Res 2008 Nov 161: 131-41 |
| PMID | 18922583 |
| Title | Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. |
| Abstract | The relationship is examined of the dopamine D2 receptor (DRD2) polymorphism (TaqIA, TaqIB, -141 C Ins/Del) and the catechol-O-methyltransferase (COMT) polymorphism (A-278G, G158A) to the risk of antipsychotic-induced extrapyramidal symptoms (EPS) in schizophrenia and bipolar disorders. Participants comprised 80 cases presenting with EPS (Simpson-Angus Scale score >3) and 188 controls presenting without EPS (Simpson-Angus Scale score |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 298 | Schizophr. Res. 2008 Dec 106: 258-64 |
| PMID | 18823757 |
| Title | Association of Sult4A1 SNPs with psychopathology and cognition in patients with schizophrenia or schizoaffective disorder. |
| Abstract | A number of genes located on chromosome 22q11-13, including catechol-O-methyltransferase (COMT), are potential schizophrenia susceptibility genes. Recently, the sulfotransferase-4A1 (Sult4A1) locus within chromosome 22q13 was reported to be linked to schizophrenia in a family TDT study. Sult4A1 is related to metabolism of monoamines, particularly dopamine and norepinephrine, both of which have been implicated in the pathophysiology of the psychopathology and cognitive dysfunction components of schizophrenia. An available, prospectively collected data base was interrogated to determine how three Sult4A1 SNPs: rs138060, rs138097, and rs138110, previously shown to be associated with schizophrenia might be associated with psychopathology, cognition, and quality of life in a sample of 86 Caucasian patients with schizophrenia or schizoaffective disorder. The majority of patients met criteria for treatment resistant schizophrenia and had been drug-free for one week or longer at the time of evaluation. The major findings were: 1) patients heterozygous (T/G) for rs138060 had significantly worse Brief Psychiatric Rating Scale (BPRS) Total and anxiety/depression sub-scale scores, and higher Scale for the Assessment of Positive Symptoms (SAPS) Total scores than G/G homozygous patients; and 2) patients heterozygous (A/G) for rs138097 demonstrated significantly worse performance on neuropsychological testing, specifically on tests of executive function and working memory, compared to patients homozygous for the G and A alleles. RS138110 was unrelated to psychopathology and cognition. These results provide the first evidence of how genetic variation in Sult4A1 may be related to clinical symptoms and cognitive function in schizophrenia, and permit future studies to attempt to replicate these potentially important findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 299 | Dev Disabil Res Rev 2008 -1 14: 59-68 |
| PMID | 18636637 |
| Title | Genes, brain development and psychiatric phenotypes in velo-cardio-facial syndrome. |
| Abstract | Velo-cardio-facial syndrome (VCFS) has been in the focus of intensive research over the last 15 years. The syndrome represents a homogeneous model for studying the effect of a decreased dosage of genes on the development of brain structure and function and, consequently, on the emergence of schizophrenia-like psychotic disorder. In this review, we describe the psychiatric phenotype of children, adolescents, and young adults with VCFS. We redefine the concept of "behavioral phenotype" and suggest that psychosis fulfills the criteria of a behavioral phenotype of the syndrome. Identifying the risk factors for the emergence of psychosis in VCFS is a major goal of several large-scale longitudinal studies that are currently underway. We review the knowledge gained so far about risk factors for psychosis in VCFS, including early neuropsychiatric symptoms, development of brain structure and function, and the effect of a reduced dosage of genes from the 22q11 deletion region. Although the brain structure in subjects with VCFS is not drastically different from typically developing controls, newer imaging modalities that measure white matter tracts, cortical thickness, and cortical gyrification are likely to identify more subtle and specific neuroanatomical substrates of the syndrome. Among the 24 genes within the deletion region, the role of catechol-O-methyltransferase (COMT) on the VCFS phenotype has been investigated in depth. The findings suggest that because of haploinsufficiency of the COMT gene individuals with VCFS are exposed to a high level of prefrontal dopamine, and this interferes with their prefrontal cognitive functioning and may contribute to their high rate of psychosis and other psychiatric disorders. The other genes and environmental factors that shape the unique neuropsychiatric phenotype of VCFS are yet to be discovered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 300 | J Abnorm Psychol 2008 Nov 117: 788-98 |
| PMID | 19025226 |
| Title | Anhedonia as a phenotype for the Val158Met COMT polymorphism in relatives of patients with schizophrenia. |
| Abstract | The Val(158)Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with aspects of schizophrenia that are possibly related to the disorder's pathogenesis. The present study investigated the Val(158)Met polymorphism in relation to anhedonia--a construct central to negative schizotypy. Anhedonia and other schizotypal characteristics were assessed in relatives of patients with schizophrenia, relatives of patients with bipolar disorder, and nonpsychiatric controls using the Chapman schizotypy scales and the schizotypal Personality Questionnaire. Compared with controls, relatives of individuals with schizophrenia had elevated scores on Chapman scales for social anhedonia and physical anhedonia, while relatives of patients with bipolar disorder exhibited only increased scores on the Social Anhedonia Scale. As a group, relatives of patients with schizophrenia who were homozygous for the val allele of the COMT polymorphism showed the highest elevations in self-reported social and physical anhedonia. Associations with the COMT polymorphism were absent in relatives of patients with bipolar disorder and control participants. Findings suggest that anhedonia is manifest in individuals who carry genetic liability for schizophrenia and is associated with the Val(158)Met polymorphism of the COMT gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 301 | J Abnorm Psychol 2008 Nov 117: 788-98 |
| PMID | 19025226 |
| Title | Anhedonia as a phenotype for the Val158Met COMT polymorphism in relatives of patients with schizophrenia. |
| Abstract | The Val(158)Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with aspects of schizophrenia that are possibly related to the disorder's pathogenesis. The present study investigated the Val(158)Met polymorphism in relation to anhedonia--a construct central to negative schizotypy. Anhedonia and other schizotypal characteristics were assessed in relatives of patients with schizophrenia, relatives of patients with bipolar disorder, and nonpsychiatric controls using the Chapman schizotypy scales and the schizotypal Personality Questionnaire. Compared with controls, relatives of individuals with schizophrenia had elevated scores on Chapman scales for social anhedonia and physical anhedonia, while relatives of patients with bipolar disorder exhibited only increased scores on the Social Anhedonia Scale. As a group, relatives of patients with schizophrenia who were homozygous for the val allele of the COMT polymorphism showed the highest elevations in self-reported social and physical anhedonia. Associations with the COMT polymorphism were absent in relatives of patients with bipolar disorder and control participants. Findings suggest that anhedonia is manifest in individuals who carry genetic liability for schizophrenia and is associated with the Val(158)Met polymorphism of the COMT gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 302 | Brain Behav. Immun. 2008 Oct 22: 1103-7 |
| PMID | 18571372 |
| Title | Association between cognitive functioning, exposure to Herpes Simplex Virus type 1, and the COMT Val158Met genetic polymorphism in adults without a psychiatric disorder. |
| Abstract | Previous studies have documented that serologic evidence of infection with the neurotropic human herpesvirus Herpes Simplex Virus type 1 (HSV-1) is associated with increased levels of cognitive dysfunction in individuals with schizophrenia or bipolar disorder. The catechol-o-methyl transferase (COMT) Val158Met polymorphism has also been associated with cognitive dysfunction in individuals with psychiatric disorders as well as in some control populations. We examined whether these factors are independently associated with cognitive functioning in adults without a history of a psychiatric disorder. A total of 240 individuals were evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Wisconsin Card Sorting Test (WCST). We measured IgG antibodies to HSV-1 by enzyme immunoassay and employed real time PCR to measure COMT Val158Met genotypes. Serological evidence of HSV-1 was significantly associated with a lower RBANS total score independent of demographic factors and the COMT Val158Met genotype. The strongest association between cognitive functioning and serological evidence of HSV-1 infection was with the domain of delayed memory. Serological evidence of HSV-1 infection was associated with an 18-fold increased odds of having a severe impairment in this domain. The Val/Val genotype of the COMT Val158Met polymorphism was also significantly associated with the RBANS total score and with a moderate decrease in the domain of attention. Infections with HSV-1 and the COMT Val158Val genotype are risk factors for cognitive deficits in non-elderly persons without a psychiatric disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 303 | Hum. Mutat. 2008 Jul 29: 891-902 |
| PMID | 18444257 |
| Title | Mutations in human monoamine-related neurotransmitter pathway genes. |
| Abstract | Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 304 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1314-8 |
| PMID | 18384078 |
| Title | Association study of candidate variants of COMT with neuroticism, anxiety and depression. |
| Abstract | The Val158Met polymorphism of the gene encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with psychiatric disorders, but replication has been inconsistent including both sex limitation and heterogeneity of the associated allele. In this study we investigate the association between three SNPs from COMT and anxiety and depression disorders and neuroticism all measured within the same study sample. Participants were selected as sibling pairs (or multiples) that were either concordant or discordant for extreme neuroticism scores from a total sample of 18,742 Australian twin individuals and their siblings. All participants completed the Composite International Diagnostic Interview (CIDI) from which diagnoses of DSM-IV depression and anxiety disorders were determined. Of the participants, 674 had a diagnosis of anxiety and/or depression from 492 families. Study participants (n = 2,045 from 987 families) plus, where possible, their parents were genotyped for rs737865, rs4680 (Val158Met), and rs165599. Using family based tests we looked for association between these variants and neuroticism, depression, anxiety, panic disorder and agarophobia (PDAG) and obsessive compulsive disorder. We found no convincing evidence for association either in allelic or genotypic tests for the total sample or when the sample was stratified by sex. Haplotype T-G-G showed weak association (P = 0.042) with PDAG before correction for multiple testing; association between this haplotype and schizophrenia has been previously reported in an Australian sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 305 | Eur. Psychiatry 2008 Apr 23: 219-22 |
| PMID | 18328676 |
| Title | Evidence that the COMTVal158Met polymorphism moderates subclinical psychotic and affective symptoms in unaffected first-degree relatives of patients with schizophrenia. |
| Abstract | Psychotic patients with COMT(Val158Met) Met alleles were recently found to display more intense psychotic and affective responses to daily life stressors. We aimed to test the hypothesis that the Met allele is implicated in the development of affective and psychotic symptomatology in subjects genetically at risk for schizophrenia, by testing if unaffected first-degree relatives of patients with schizophrenia who share a Met allele have greater concordance of symptomatology than relatives not sharing a Met allele. Unaffected relatives (n=38) were arranged in as many genetically related pairs as possible (n=26), and Met-sharing between Index Unaffected Subject (IUS) and Related Unaffected Subject (RUS) was assessed. Symptomatology was assessed with the Brief Psychiatric Rating Scale (BPRS) total score. Multilevel regression revealed an interaction between RUS BPRS score and Met-sharing in the model of IUS BPRS score (interaction chi(2)=3.78, p=0.05). Stratified analyses revealed that IUS-RUS total BPRS scores were significantly associated in the case of Met-sharing (B=0.57, 95% CI: 0.22-0.93, p=0.002), but were not when there was no Met-sharing. These findings support the hypothesis that the Met allele may be involved in the causation of psychopathology, at least in populations with a genetic predisposition to psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 306 | Schizophr. Res. 2008 Mar 100: 316-24 |
| PMID | 18201871 |
| Title | Personality in relation to genetic liability for schizophrenia and bipolar disorder: differential associations with the COMT Val 108/158 Met polymorphism. |
| Abstract | schizophrenia and bipolar disorder may share aspects of genetic etiology. Evidence supports the Val 108/158 Met polymorphism of the Catechol-o-Methyltransferase (COMT) gene as potentially contributing to the etiology of both disorders. To determine whether the COMT gene is associated with personality traits related to genetic risk for either schizophrenia or bipolar disorder, we examined dimensions of personality psychopathology in biological relatives of individuals with the disorders. Specifically, we contrasted personality characteristics of first-degree relatives of people with schizophrenia, first-degree relatives of people with bipolar-I disorder, and nonpsychiatric control participants using scores from the Dimensional Assessment of Personality Pathology-Brief Questionnaire (DAPP-BQ). We also characterized the COMT Val 108/158 Met polymorphism of subjects. Compared to controls, relatives of schizophrenia patients scored lower on stimulus seeking and higher on restrictive expression and social avoidance. Compared to relatives of bipolar patients, relatives of schizophrenia patients had lower scores on narcissism, rejectionality (i.e., rejection of ideas of others), stimulus seeking, passive-aggressive oppositionality, and self-harm. The subset of relatives of schizophrenia patients who were COMT val homozygotes exhibited lower scores on narcissism, rejectionality, and stimulus seeking than met homozygote relatives of schizophrenia patients and control participants. Although relatives of bipolar patients showed scale elevations consistent with emotional dysregulation, the scores failed to be associated with the Val 108/158 Met polymorphism. Abnormally low narcissism and rejectionality in val homozygote relatives of schizophrenia patients suggests that the val allele of the COMT polymorphism may be associated with an underdeveloped self-concept phenomenologically similar to made volition and passivity experiences comprising first-rank symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 307 | Schizophr Bull 2008 Nov 34: 1231-9 |
| PMID | 18199630 |
| Title | Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test. |
| Abstract | Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val108/158Met on executive attention, using ANT. We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val108/158Met genotype on executive attention as assessed by the ANT. Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val108/158Met on cognitive performance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 308 | Br. J. Pharmacol. 2008 Mar 153 Suppl 1: S120-4 |
| PMID | 18193072 |
| Title | Neuroimaging and molecular genetics of schizophrenia: pathophysiological advances and therapeutic potential. |
| Abstract | There is impressive evidence for the involvement of several genetic risk factors in the aetiopathogenesis of schizophrenia. Most of these genes impact on neuropharmacological systems. Examining their relationship with brain imaging indices is arguably the best currently available method of examining these effects in vivo. In a sample of young, initially healthy people at high genetic risk of schizophrenia brain structure was measured with structural magnetic resonance imaging (sMRI) and brain function was indexed with neuropsychological tests and functional MRI. Regular detailed clinical assessments established whether subjects had developed psychotic symptoms and/or schizophrenia itself. The Catechol-O-Methyl Transferase (COMT) Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with this allele had reduced grey matter density in anterior cingulate cortex and increased fMRI activation in lateral prefrontal cortex and anterior and posterior cingulate. The risk allele in the Neuregulin 1 (NRG1) promoter region, on the other hand, was associated with the development of psychotic symptoms, decreased premorbid IQ and decreased activation of pre-frontal and temporal lobe regions. The NRG1 gene appears to be a risk factor for an extended or intermediate phenotype, while the COMT Val allele, which decreases the rate at which cortical dopamine is degraded compared to the Met allele, is associated with an increased risk of schizophrenia in subjects at increased familial risk. We provide examples of how these advances in our knowledge could lead to the development of new treatments for psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 309 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Sep 147B: 990-5 |
| PMID | 18186041 |
| Title | Interactive effects of COMT Val108/158Met and MTHFR C677T on executive function in schizophrenia. |
| Abstract | schizophrenia is characterized by heritable deficits in executive function. Two common, functional polymorphisms, catechol-O-methyltransferase (COMT) Val108/158Met and methylenetetrahydrofolate reductase (MTHFR) C677T, have separately been associated with executive function performance in schizophrenia. Given the closely related biochemistry of MTHFR and COMT, it is plausible that the T and Val alleles act synergistically to impair executive function. This investigation of 185 outpatients with schizophrenia examined the interactive effects of these two polymorphisms on Wisconsin Card Sorting Task (WCST) performance. Two WCST measures consistently associated with schizophrenia, perseverative errors and inability to generate categories, were contrasted among compound COMT-MTHFR genotype groups. Individuals homozygous for the COMT Val allele who also carried at least one copy of the MTHFR T allele exhibited a significantly higher percentage of perseverative errors than patients in the other genotype groups. While the T allele also exerted a negative effect on category generation, COMT genotype did not contribute to category performance. It is plausible that cumulative effects of the MTHFR T and COMT Val alleles on intracellular methylation profiles and prefrontal dopamine transmission underlie their interactive effect on perseverative errors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 310 | Anal. Chem. 2008 Feb 80: 588-96 |
| PMID | 18181582 |
| Title | Design of electrochemical biosensor systems for the detection of specific DNA sequences in PCR-amplified nucleic acids related to the catechol-O-methyltransferase Val108/158Met polymorphism based on intrinsic guanine signal. |
| Abstract | Psychiatric disorders are common and complex diseases that show polygenic and multifactorial heredity. A single nucleotide polymorphism (Val108/158Met) in the catechol-O-methyl transferase (COMT) gene is related to many psychiatric disorders such as schizophrenia, alcoholism, bipolar disorder, and obsessive-compulsive disorder. schizophrenia is a complex disorder and a single nucleotide polymorphism (Val108/158Met) at the COMT gene is related to schizophrenia susceptibility. A novel hybridization-based disposable electrochemical DNA biosensor for the detection of a common functional polymorphism in the COMT gene from polymerase chain reaction (PCR) amplicons has been described without using an external label. This developed technology combined with a disposable carbon graphite electrode and differential pulse voltammetry was performed by using short synthetic oligonucleotides and PCR amplicons in length 203 bp to measure the change of guanine oxidation signal obtained at approximately +1.0 V after DNA hybridization between probe and target (synthetic target or denatured PCR samples). COMT-specific oligonucleotides were immobilized onto the carbon surface with a simple adsorption method in two different modes: (a) Guanine-containing targets were attached or (b) inosine-substituted probes were attached onto an electrode. By controlling the surface coverage of the target DNA, the hybridization event between the probes and their synthetic targets or specific PCR products was optimized. The wild-type or polymorphic allele-specific probes/targets were also interacted with an equal amount of noncomplementary and one-base mismatch-containing DNAs in order to measure the sensor selectivity. The decrease or appearance in the intrinsic guanine signal simplified the detection procedure and shortened the assay time because protocol eliminates the label-binding step. The nonspecific binding effects were minimized by using sodium dodecyl sulfate with different washing methods. The Val108/158Met COMT genotype detection were performed with real samples containing wild-type (healthy controls), polymorphic (mutant type), and heterozygous PCR products. The detection limit (S/N = 3) of the biosensor was 2.44 pmol of target sequence in the 30-muL samples. Analytical performance of the sensor is described, along with future prospects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 311 | Hum. Mol. Genet. 2008 Mar 17: 747-58 |
| PMID | 18045777 |
| Title | A network of dopaminergic gene variations implicated as risk factors for schizophrenia. |
| Abstract | We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 312 | Behav. Brain Res. 2008 Mar 187: 428-32 |
| PMID | 18037170 |
| Title | D2 receptor density and prepulse inhibition in humans: negative findings from a molecular genetic approach. |
| Abstract | There is plenty of evidence from schizophrenia research and psychopharmacological experiments showing the influence of the dopaminergic neurotransmission on the prepulse inhibition (PPI). A lot of insights into the underlying neural mechanisms of the PPI have been gained from animal models, which are in need to be validated in humans. Due to new technological advances, findings from psychopharmacological challenge tests can now be verified with techniques from molecular genetics which provide an elegant non-invasive approach. To close the gap between animal research and research in humans in this field a molecular genetic approach was applied to investigate the neural mechanisms of the PPI in healthy subjects. In N=96 female participants recruited out of a sample of N=800 subjects according to their genotypes we tested the association between the DRD2 Taq Ia and the COMT Val158Met polymorphisms, and the magnitude of the eye-blink reflex in an acoustic PPI paradigm. Neither significant influences of both dopaminergic single nucleotide polymorphisms nor an epistasis effect could be detected. Although findings do not support the hypothesis that two of the most prominent dopaminergic candidate loci (DRD2 Taq Ia and COMT Val158Met) effect PPI the study does not exclude the relevance of the dopaminergic system in general. Further molecular genetic studies investigating other variants on dopaminergic genes have to be conducted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 313 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Mar 147B: 223-7 |
| PMID | 17948281 |
| Title | Divergent backward masking performance in schizophrenia and bipolar disorder: association with COMT. |
| Abstract | schizophrenia has been reliably associated with impairments in backward masking performance, while bipolar disorder has less consistently been tied to such a deficit. To examine the genetic determinants of visual perception abnormalities in schizophrenia and bipolar disorder, this study evaluated the diagnostic specificity of backward masking performance deficits and whether masking deficits were associated with catechol-O-methyl transferase (COMT) genotype. A location-based backward masking task, which equated participants on the perceptual intensity of stimuli, was completed by 41 schizophrenia outpatients, 28 bipolar outpatients, and 43 nonpsychiatric controls. COMT genotype data were available for 39 schizophrenia outpatients, 28 bipolar outpatients, and 20 nonpsychiatric controls. schizophrenia patients demonstrated impaired backward masking performance compared to controls and bipolar patients. A group by COMT genotype interaction was detected with schizophrenia Met homozygotes performing more poorly than control and bipolar Met homozygotes, and worse than Val homozygote and heterozygote schizophrenia patients. This study provides novel evidence for differential effects of the COMT gene on neural systems underlying visual perception in schizophrenia and bipolar disorder. The COMT Met allele may be associated with deficits in schizophrenia that are unrelated to neural systems supporting sustained attention or working memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 314 | Biol. Psychiatry 2008 Jan 63: 72-9 |
| PMID | 17707347 |
| Title | Genetic variation in catechol-O-methyltransferase: effects on working memory in schizophrenic patients, their siblings, and healthy controls. |
| Abstract | Catechol-O-methyltransferase (COMT) val(108/158)met (rs4680) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865, rs165599, and rs2097603. In a large sample, we examined whether these SNPs affect WM. schizophrenic probands (n = 325), their nonpsychotic siblings (n = 359), and normal control subjects (n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val(108/158)met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val(108/158)met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling. We extended earlier findings of a val(108/158)met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val(108/158)met effect in a nonlinear manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 315 | Genes Brain Behav. 2008 Feb 7: 61-9 |
| PMID | 17504246 |
| Title | Genetic variation in COMT and PRODH is associated with brain anatomy in patients with schizophrenia. |
| Abstract | Haploinsufficiency of 22q11 genes including catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH) may result in structural and functional brain abnormalities and increased vulnerability to schizophrenia as observed in patients with microdeletions of 22q11. Thus, COMT and PRODH could be modifier genes for schizophrenia. We examined association of polymorphisms in COMT and PRODH with brain anatomy in young patients with schizophrenia and schizoaffective disorder. We acquired structural magnetic resonance imaging data from 51 male patients and genotyped two single nucleotide polymorphisms (SNPs) in the COMT gene and three in the PRODH gene. Statistical Parametric Mapping software and optimized voxel-based morphometry were used to determine regional gray matter (GM) and white matter (WM) density differences, and total GM and WM volume differences between genotype groups. Two nonsynonymous SNPs in the PRODH gene were associated with bilateral frontal WM density reductions and an SNP in the P2 promoter region of COMT (rs2097603) was associated with GM increase in the right superior temporal gyrus. Furthermore, we found evidence for COMT and PRODH epistasis: in patients with a COMT Val allele (rs4680) and with one or two mutated PRODH alleles, we observed increased WM density in the left inferior frontal lobe. Our results suggest that genetic variation in COMT and PRODH has significant effects on brain regions known to be affected in schizophrenia. Further research is needed to investigate the role of 22q11 genes on brain structure and function and their role in vulnerability for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 316 | Psychol Med 2008 Jan 38: 89-100 |
| PMID | 17493297 |
| Title | Effects of a functional COMT polymorphism on brain anatomy and cognitive function in adults with velo-cardio-facial syndrome. |
| Abstract | Velo-cardio-facial syndrome (VCFS) is associated with deletions at chromosome 22q11, abnormalities in brain anatomy and function, and schizophrenia-like psychosis. Thus it is assumed that one or more genes within the deleted region are crucial to brain development. However, relatively little is known about how genetic variation at 22q11 affects brain structure and function. One gene on 22q11 is catechol-O-methyltransferase (COMT): an enzyme that degrades dopamine and contains a functional polymorphism (Val158Met) affecting enzyme activity. Here, we investigated the effect of COMT Val158Met polymorphism on brain anatomy and cognition in adults with VCFS. The COMT Val158Met polymorphism was genotyped for 26 adults with VCFS on whom DNA was available. We explored its effects on regional brain volumes using hand tracing approaches; on regional grey- and white-matter density using computerized voxel-based analyses; and measures of attention, IQ, memory, executive and visuospatial function using a comprehensive neuropsychological test battery. After corrections for multiple comparisons Val-hemizygous subjects, compared with Met-hemizygotes, had a significantly larger volume of frontal lobes. Also, Val-hemizygotes had significantly increased grey matter density in cerebellum, brainstem, and parahippocampal gyrus, and decreased white matter density in the cerebellum. No significant effects of COMT genotype on neurocognitive performance were found. COMT genotype effects on brain anatomy in VCFS are not limited to frontal regions but also involve other structures previously implicated in VCFS. This suggests variation in COMT activity is implicated in brain development in VCFS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 317 | Schizophr Bull 2008 Nov 34: 1231-9 |
| PMID | 18199630 |
| Title | Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test. |
| Abstract | Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val108/158Met on executive attention, using ANT. We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val108/158Met genotype on executive attention as assessed by the ANT. Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val108/158Met on cognitive performance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 318 | Biol. Psychiatry 2008 Jan 63: 72-9 |
| PMID | 17707347 |
| Title | Genetic variation in catechol-O-methyltransferase: effects on working memory in schizophrenic patients, their siblings, and healthy controls. |
| Abstract | Catechol-O-methyltransferase (COMT) val(108/158)met (rs4680) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865, rs165599, and rs2097603. In a large sample, we examined whether these SNPs affect WM. schizophrenic probands (n = 325), their nonpsychotic siblings (n = 359), and normal control subjects (n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val(108/158)met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val(108/158)met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling. We extended earlier findings of a val(108/158)met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val(108/158)met effect in a nonlinear manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 319 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1491-5 |
| PMID | 18579277 |
| Title | Association between dopamine-related polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients. |
| Abstract | Hyperprolactinemia is an inevitable consequence of treatment with antipsychotic agents to some extent because prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that polymorphisms of the dopamine receptors are associated with therapeutic response to antipsychotics. Thus, we studied the effects of major polymorphisms of dopamine-related genes on plasma concentration of prolactin. Subjects were 174 schizophrenic patients (68 males, 106 females) receiving 3 mg twice daily of risperidone for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. Five dopamine-related polymorphisms (Taq1A, -141C ins/del for DRD2, Ser9Gly for DRD3, 48 bp VNTR for DRD4, Val158Met for COMT) were identified. The mean (+/-SD) plasma concentration of prolactin in females was significantly higher than males (54.3+/-27.2 ng/ml versus 126.8+/-70.2 ng/ml, p<0.001). No dopamine-related polymorphisms differed the plasma concentration of prolactin in males or females. Multiple regression analyses including plasma drug concentration and age revealed that plasma concentration of prolactin correlated with gender (standardized partial correlation coefficients (beta)=0.551, p<0.001) and negatively with age (standardized beta=-0.202, p<0.01). No correlations were found between prolactin concentration and dopamine-related polymorphisms. These findings suggest that plasma prolactin concentrations in females are much higher than in males but the dopamine-related variants are not predominantly associated with plasma concentration of prolactin. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 320 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Sep 147B: 898-902 |
| PMID | 18213617 |
| Title | Putative role of the COMT gene polymorphism (Val158Met) on verbal working memory functioning in a healthy population. |
| Abstract | Working memory has been described as a neurocognitive probe of prefrontal brain functioning. Genetic variability related with catechol-O-methyltransferase (COMT) gene (Val158Met polymorphism) has received increasing attention as a possible modulator of working memory tasks in both schizophrenic patients and healthy subjects, although inconsistencies across studies have been found. This may be related to the existence of different working memory components, processes and modalities, which may have different sensitivities to subtle changes in dopamine levels and, therefore, the effect of the underlying COMT Val158Met genetic variability. To test this out a large sample of 521 healthy individuals from the general population were tested on the WCST and three working memory tasks that cover the assessment of verbal and spatial working modalities as well as different components and processes (Letter and Number Sequencing, CPT-IP, Backwards Visual Span). All individuals were genotyped for the rs4680 (Val158Met) polymorphism at the COMT gene. Met carriers showed near-significant better performance in the LNS compared with Val/Val individuals (F = 3.9, df = 1, P = 0.046). Moreover, the analysis for linear trend found that Met allele carriers showed significantly better performance than Val/Val individuals (B = 0.58 P = 0.031), although evidence for a linear trend was not found. None of the WCST indices differed among genotypes. Consistent with the hypothesis that Val158Met polymorphism (COMT gene) might account for individual differences on dopamine-dependent prefrontally related neurocognitive functions, the Letter-Number Sequencing task, which requires not only maintenance but also active manipulation of information seemed to be more sensitive to the disadvantageous Val/Val genotype in a large non-clinical sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 321 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Aug 33: 1064-9 |
| PMID | 19508883 |
| Title | ARVCF single marker and haplotypic association with schizophrenia. |
| Abstract | We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3' downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3' region of the ARVCF gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 322 | Psychiatry Res 2009 Sep 169: 173-5 |
| PMID | 19647329 |
| Title | COMT val(158)met genotype and smooth pursuit eye movements in schizophrenia. |
| Abstract | The association between the catechol-O-methyltransferase (COMT) val(158)met polymorphism (rs4680) and smooth pursuit eye movements (SPEM) was investigated in 110 schizophrenia patients and 96 controls. Patients had lower steady-state pursuit gain and made more frequent saccades than controls. Genotype was not associated with schizophrenia or SPEM, in either group or the combined sample. SPEM deficits in schizophrenia appear to be determined by genotypes other than rs4680, although the study may have lacked power to detect small effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 323 | Pharmacogenomics J. 2009 Oct 9: 311-8 |
| PMID | 19451915 |
| Title | Candidate-gene association analysis of response to risperidone in African-American and white patients with schizophrenia. |
| Abstract | Clinical trial data were evaluated for the association between 22 single-nucleotide polymorphisms (SNPs) and response in acutely ill patients diagnosed with schizophrenia, schizoaffective disorder or schizophreniform disorder, who were treated with oral risperidone. All patients in the exploratory (78 African Americans) and validation (65 whites) data sets received risperidone 2-6 mg per day over 2-12 weeks. Two SNPs were found to have significant associations with response to risperidone over 2-12 weeks in both African-American and white patients and had a consistent direction of effect in both cohorts. Metabotropic glutamate receptor (GRM3) SNP, rs724226, was associated with a change in the positive and negative syndrome scale (PANSS) total response. Catechol-O-methyltransferase (COMT) SNP, rs165599, was moderately associated with a change in the PANSS Negative score. The greater prevalence of poor-responder GRM3 and COMT alleles in white versus African-American patients might have a clinical significance in evaluating the ethnic-specific response to risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 324 | Genet Test Mol Biomarkers 2009 Apr 13: 233-6 |
| PMID | 19371223 |
| Title | Association between catechol-O-methyltransferase gene polymorphism and attention-deficit hyperactivity disorder in Korean population. |
| Abstract | Recently, the relationship between allele frequency distribution and attention-deficit hyperactivity disorder (ADHD) has been actively studied. In Korea, the relationship between the genetic type and alleles for catechol-O-methyltransferase (COMT) gene has been studied in ADHD patients. ADHD was diagnosed in 60 patients according to the Diagnostic and Statistical Manual of Mental Disorders Version IV (DSM-IV) diagnostic criteria and Schedule for Affective Disorders and schizophrenia for School-Age Children--Present and Lifetime Version (K-SADS-PL), and they were selected for the study. For the control group, normal volunteers were chosen. Blood samples were taken from the 160 subjects. DNA was extracted from blood lymphocytes, and PCR was performed for COMT NlaIII VNTR polymorphism. For the case-control analyses, allele and genotype frequencies were compared using the chi(2) method. When the ADHD group and the normal control group were compared, significant difference was seen on the COMT genetic type, but was not seen on the allele distribution. As a result, it is viewed that there is no relationship between ADHD and the COMT gene, but final decision is indefinite. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 325 | Brain Res. 2009 May 1269: 166-75 |
| PMID | 19268435 |
| Title | Dopamine-glutamate abnormalities in the frontal cortex associated with the catechol-O-methyltransferase (COMT) in schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) plays an important role in brain catecholamine metabolism. Several studies point to the involvement of COMT in schizophrenia. We applied COMT immunohistochemistry to paraffin-embedded brain sections and assessed the cell density of COMT expressing glial cells and COMT expressing neurons in the gray matter of the frontal cortex of patients with schizophrenia compared with control subjects. We found a significantly increased cell density of COMT expressing glial cells (p=0.003), but an unchanged cell density of COMT expressing neurons (p=0.778) in the gray matter of the frontal cortex of patients with schizophrenia compared with control subjects. Our study demonstrates that schizophrenia might involve increased COMT expression in glial cells in the frontal cortex, which might be associated with a neuronal-glial abnormality and a disturbed dopamine-glutamate interaction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 326 | Eur Neuropsychopharmacol 2009 Jan 19: 14-22 |
| PMID | 18824331 |
| Title | Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. |
| Abstract | S-adenosyl-methionine (SAM-e), functions as a primary methyl group donor for several metabolic compounds. Since SAM-e is involved in several metabolic processes, its administration may have a role in the amelioration of several disorders. In addition, SAM-e increases catechol-O-methyltransferase (COMT) enzyme activity, which may ameliorate aggressive symptoms in certain patients. We have therefore investigated the efficacy of SAM-e in managing schizophrenia symptomatology in patients with the low activity COMT polymorphism. Eighteen patients with chronic schizophrenia were randomly assigned to receive either SAM-e (800 mg) or placebo for 8 weeks in double-blind fashion. Results indicated some reduction in aggressive behavior and improved quality of life following SAM-e administration. Female patients showed improvement of depressive symptoms. Clinical improvement did not correlate with serum SAM-e levels. Two patients receiving SAM-e exhibited some exacerbation of irritability. This preliminary pilot short-term study cautiously supports SAM-e as an adjunct in management of aggressive behavior and quality of life impairment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 327 | Cogn Neuropsychiatry 2009 -1 14: 277-98 |
| PMID | 19634031 |
| Title | Prefrontal cognitive systems in schizophrenia: towards human genetic brain mechanisms. |
| Abstract | schizophrenia has complex genetic heritability. It is also genetically heterogeneous. To the extent that genes are associated with symptom constellations in schizophrenia, they do so by affecting the development and function of neural systems that mediate the expression of such diverse behavioral, cognitive and perceptual phenomena. The genetic mechanisms of human brain dysfunction remain to be well understood. "Imaging genetics" is an emerging field that attempts to integrate the basic biology of putative disease mechanisms with physiological correlates from the live human brain. Here, we review recent imaging genetics work on prefrontal brain systems associated with working memory and executive function - heritable traits relevant to schizophrenia. Starting with genetic variation in dopaminergic systems (e.g., COMT), we examined the modulation of prefrontal brain networks during active cognitive processing; there is also evidence that variation in the expression of dopamine-related downstream intra-cellular signaling molecules (e.g., AKT1) are implicated. Moreover, these genetic variants evidence epistasis on neuroimaging measures, lending further support to the conceptualization that non-additive combinations of multiple genes modulate active human cognitive brain mechanisms. The imaging genetics platform therefore could extend understanding of genetic mechanisms of human cognitive brain processes relevant to neuropsychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 328 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 329 | Biol. Psychiatry 2009 Jun 65: 1048-54 |
| PMID | 19159868 |
| Title | Evidence of epistasis between the catechol-O-methyltransferase and aldehyde dehydrogenase 3B1 genes in paranoid schizophrenia. |
| Abstract | schizophrenia is a common yet severe psychiatric condition characterized by complex genetic mechanism and diverse clinical presentations. Our previous study indicated that the combined effect of two intronic single nucleotide polymorphisms (SNPs), which are located in the catechol-O-methyltransferase (COMT) and aldehyde dehydrogenase 3B1 (ALDH3B1) genes, respectively, conferred genetic risk to paranoid schizophrenia. To further explore the precise mechanism of the COMT and ALDH3B1 interaction involved in the pathophysiology of schizophrenia, we scanned all possible functional SNPs within these two genes by polymerase chain reaction (PCR)-based genotyping analysis in 540 paranoid schizophrenic patients and 660 control subjects from a Han Chinese population. We also determined the effects of schizophrenia-associated SNPs on the development of psychotic symptoms, P300 event-related potential components induced by an auditory odd-ball task, and gene expression examined by quantitative real-time PCR analysis. The major findings of this study were that, among the individuals carrying the rs3751082 A allele in the ALDH3B1 gene, the rs4633 T allele in the COMT gene was associated with susceptibility to paranoid schizophrenia (p = .004), development of hallucination (p = 5.141 E-5), delay of P300 latency in both patients (p = .006) and control subjects (p = .02), and increased expression of the COMT gene in control subjects (p = .002). However, the rs4633 T allele did not show any association in the rs3751082 G/G genotype carriers. These findings provided convincing evidence that epistasis between the COMT and ALDH3B1 genes plays an important role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 330 | Psychol Med 2009 Nov 39: 1783-97 |
| PMID | 19573260 |
| Title | The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis. |
| Abstract | Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis. A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family. The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes. Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 331 | Pharmacogenomics 2009 Feb 10: 277-91 |
| PMID | 19207030 |
| Title | Genetic susceptibility to schizophrenia: role of dopaminergic pathway gene polymorphisms. |
| Abstract | We investigated 16 polymorphisms from three genes, dopamine receptor D2 (DRD2), catechol-O-methyl transferase (COMT) and brain derived neurotrophic factor (BDNF), which are involved in the dopaminergic pathways, and have been reported to be associated with susceptibility to schizophrenia and response to antipsychotic therapy. Single-locus association analyses of these polymorphisms were carried out in 254 patients with schizophrenia and 225 controls, all of southern Indian origin. Additionally, multifactor-dimensionality reduction analysis was performed in 422 samples (243 cases and 179 controls) to examine the gene-gene interactions and to identify combinations of multilocus genotypes associated with either high or low risk for the disease. Our results demonstrated initial significant associations of two SNPs for DRD2 (rs11608185, genotype: chi(2) = 6.29, p-value = 0.043; rs6275, genotype: chi(2) = 8.91, p-value = 0.011), and one SNP in the COMT gene (rs4680, genotype: chi(2) = 6.67, p-value = 0.035 and allele: chi(2) = 4.75, p-value = 0.029; odds ratio: 1.33, 95% confidence interval: 1.02-1.73), but not after correction for multiple comparisons indicating a weak association of individual markers of DRD2 and COMT with schizophrenia. Multifactor-dimensionality reduction analysis suggested a two locus model (rs6275/DRD2 and rs4680/COMT) as the best model for gene-gene interaction with 90% cross-validation consistency and 42.42% prediction error in predicting disease risk among schizophrenia patients. The present study thus emphasizes the need for multigene interaction studies in complex disorders such as schizophrenia and to understand response to drug treatment, which could lead to a targeted and more effective treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 332 | J. Hum. Genet. 2009 Dec 54: 709-12 |
| PMID | 19881467 |
| Title | Association analysis of COMT polymorphisms with schizophrenia and smooth pursuit eye movement abnormality. |
| Abstract | schizophrenia is a multifactorial disorder characterized by the contribution of multiple susceptibility genes that may act in conjunction with epigenetic processes and environmental factors. The catechol-O-methyltransferase (COMT) gene, which is located in the 22q11 microdeletion, has been considered as a candidate gene for schizophrenia because of its ability to degrade catecholamines, including dopamine. In a genetic analysis, neurophysiological endophenotype in schizophrenia, such as smooth pursuit eye movement (SPEM) disturbance, is considered to be a good trait marker, because it may be under more direct genetic control. This study was performed to examine the genetic association of COMT polymorphisms with the risk of schizophrenia and SPEM abnormality in a Korean population. Six single-nucleotide polymorphisms of COMT were genotyped by TaqMan assay. Their genetic effects on the risk of schizophrenia were analyzed in 354 patients and 396 controls using chi(2) analyses. Among the schizophrenic patients, 166 subjects were selected for association analyses of COMT polymorphisms with SPEM abnormality. From the six COMT polymorphisms, rs6267 showed an association with the reduced risk of schizophrenia after correction (P(corr) = 0.02). In analysis of SPEM abnormality, no significant associations were detected with COMT polymorphisms. The results of the present study provide the evidence that in a Korean population, COMT on the 22q11 locus is likely involved in the development of schizophrenia, but not in the SPEM function abnormality. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 333 | Schizophr. Res. 2009 Dec 115: 182-90 |
| PMID | 19836927 |
| Title | Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): a cross-sectional and longitudinal study. |
| Abstract | 22q11.2 deletion syndrome (22q11DS) is associated with an increased susceptibility to develop schizophrenia. Despite a large body of literature documenting abnormal brain structure in 22q11DS, cerebral changes associated with brain maturation in 22q11DS remained largely unexplored. To map cortical maturation from childhood to adulthood in 22q11.2 deletion syndrome, we used cerebral MRI from 59 patients with 22q11DS, aged 6 to 40, and 80 typically developing controls; three year follow-up assessments were also available for 32 patients and 31 matched controls. Cross-sectional cortical thickness trajectories during childhood and adolescence were approximated in age bins. Repeated-measures were also conducted with the longitudinal data. Within the group of patients with 22q11DS, exploratory measures of cortical thickness differences related to COMT polymorphism, IQ, and schizophrenia were also conducted. We observed deviant trajectories of cortical thickness changes with age in patients with 22q11DS. In affected preadolescents, larger prefrontal thickness was observed compared to age-matched controls. Afterward, we observed greater cortical loss in 22q11DS with a convergence of cortical thickness values by the end of adolescence. No compelling evidence for an effect of COMT polymorphism on cortical maturation was observed. Within 22q11DS, significant differences in cortical thickness were related to cognitive level in children and adolescents, and to schizophrenia in adults. Deviant trajectories of cortical thickness from childhood to adulthood provide strong in vivo cues for a defect in the programmed synaptic elimination, which in turn may explain the susceptibility of patients with 22q11DS to develop psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 334 | Med. Sci. Monit. 2009 Sep 15: CR484-9 |
| PMID | 19721400 |
| Title | Association between COMT gene and Chinese male schizophrenic patients with violent behavior. |
| Abstract | Haplotype analysis is hypothesized as having better power than individual SNPs in detecting the association between genotype and phenotype, but this approach has rarely been used in studies of the genetics of violent behavior in schizophrenia. The aim of this study was to further examine the role of the COMT gene in violent behavior. Both individual SNP and haplotype were used to explore associations between COMT polymorphisms and violent behavior in 252 patients with violent behavior and 332 patients without violent behavior of Chinese Han schizophrenics. Then the association between a three-marker haplotype (SNPs rs4680, rs737865, and rs165599) and violent behavior was explored by performing haplotype analysis using SHEsis and PHASE. Finally, the Modified Overt Aggression Scale (MOAS) was used to assess the aggressive or violent behaviors of the patients. No association was found between the individual SNPs and violent behavior in schizophrenia. However, an association was found between haplotypes and violent behavior. The frequency of the haplotype A-A-G was higher in the case group and that of haplotype G-G-A was higher in the control group. Furthermore, the patients with haplotype A-A-G scored higher on the "physical aggression against objects" subscale of the MOAS than those with the haplotype G-G-A in the case group. There is an association between COMT gene and violent behavior in Chinese schizophrenics. The haplotypes A-A-G and G-G-A may be used to predict violent behavior in Chinese schizophrenics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 335 | Biol. Psychiatry 2009 Dec 66: 997-1004 |
| PMID | 19699472 |
| Title | Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818c/g polymorphism. |
| Abstract | The functional catechol-O-methyltransferase (COMT) valine158methionine (val158met) polymorphism determines prepulse inhibition (PPI) levels and working memory performance and the effects of tolcapone on these functions. Here, we explored the effects of the synonymous COMT rs4818 C/G polymorphism and tolcapone on PPI and working memory. Thirteen G/G (low prefrontal cortex [PFC] dopamine [DA]) and 12 C/C (high PFC DA) healthy male subjects entered and completed the study. Subjects participated in two weekly sessions associated with either acute oral tolcapone (200 mg) or placebo according to a balanced, crossover, double-blind design. Prepulse inhibition was assessed with 5 dB and 15 dB above background prepulses at 30-msec, 60-msec, and 120-msec intervals. Subjective mood and working memory performance (n-back and letter-number sequencing) were also assessed. Prepulse inhibition was lower and reaction time in the n-back was slower in the G/G compared with the C/C group in the placebo condition. Tolcapone increased PPI and improved performance in both working memory tasks in the G/G group only. Baseline startle was greater in the C/C group and was not affected by tolcapone. Mood profile was worse in the C/C group and tended to deteriorate with tolcapone. Status of val158met alone could not explain these results. Catechol-O-methyltransferase haplotype analyses are essential in future research. Prepulse inhibition and working memory may both relate to PFC DA levels according to an inverted U-shaped curve function. Tolcapone could be potentially useful in the treatment of conditions with deficient sensorimotor gating and working memory such as schizophrenia and prodromal states but only in a genotype-specific manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 336 | Croat. Med. J. 2009 Aug 50: 361-9 |
| PMID | 19673036 |
| Title | Association of tagging single nucleotide polymorphisms on 8 candidate genes in dopaminergic pathway with schizophrenia in Croatian population. |
| Abstract | To perform a comprehensive evaluation of association of common genetic variants in candidate genes in the dopaminergic pathway with schizophrenia in a sample from Croatian population. A case-control association study was performed on 104 unrelated patients with schizophrenia recruited from a psychiatric hospital in Zagreb and 131 phenotypically normal Croatian subjects. Forty-nine tagging single nucleotide polymorphisms (tagSNPs) in 8 candidate genes in the dopaminergic pathway were identified from the HapMap database and tested for association. Genotyping was performed using the SNPlex platform. Statistical analysis was conducted to assess allelic and genotypic associations between cases and controls using a goodness of fit chi(2) test and trend test, respectively; adjustment for multiple testing was done by permutation based analysis. Significant allele frequency differences between schizophrenia cases and controls were observed at 4 tagSNPs located in the genes DRD5, HTR1B1, DBH, and TH1 (P<0.005). A trend test also confirmed the genotypic association (P<0.001) of these 4 tagSNPs. Additionally, moderate association (P<0.05) was observed with 8 tagSNPs on SLC6A3, DBH, DRD4, SLC6A4, and COMT. Common genetic variants in genes involved in the dopaminergic pathway are associated with schizophrenia in the populations of Caucasian descent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 337 | Proc. Natl. Acad. Sci. U.S.A. 2009 Aug 106: 13600-5 |
| PMID | 19666577 |
| Title | Epistasis between the DAT 3' UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia. |
| Abstract | Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3' UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT x DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score = 4.3; family-wise error (FWE) p = 0.03), and in healthy volunteers alone (Z-score = 4.7; FWEp = 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis x COMT x DAT nonadditive interaction in the right orbital gyrus (Z-score = 4.3; FWEp = 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score = 4.3; FWE p = 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 338 | Pharmacopsychiatry 2009 Jul 42: 141-4 |
| PMID | 19585392 |
| Title | COMT Val 158 Met polymorphism is associated with cognitive flexibility in a signal discrimination task in schizophrenia. |
| Abstract | Associations between the well-known functional single nucleotide polymorphism Val (158)Met in the gene encoding catechol- O-methyltransferase (COMT) and cognitive do-mains affected in schizophrenia are inconsistent regarding directionality and specific impact and call for a more fundamental cognitive endophenotype. Recent studies suggest that the COMT genotype contributes to cognitive flexibility, a fundamental cognitive ability that potentially influences an individual's performance in a variety of other neurocognitive tasks. We investigated the association between COMT Val (158)Met genotype and cognitive flexibility as assessed by signal discrimination in the Continuous Performance Test - Identical Pairs version in a cohort of 111 German schizophrenic patients. COMT genotype was significantly associated with signal discrimination index d' in schizophrenia. The Val/Val genotype was associated with the highest and the Met/Met genotype with the lowest scores; heterozygous individuals displayed an intermediate performance. Our data suggest that allelic variation at the COMT Val (158)Met locus may influence signal discrimination capacity in schizophrenia and confirm that Val loading, probably due to decreased prefrontal dopamine availability, is associated with greater cognitive flexibility, which in turn may influence other cognitive measures that have been associated with COMT to date. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 339 | Biol. Psychiatry 2009 Sep 66: 614-20 |
| PMID | 19545856 |
| Title | Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study. |
| Abstract | Prepulse inhibition (PPI) of the acoustic startle response (ASR) is an operational measure of sensorimotor gating and a promising endophenotype of schizophrenia. We have recently shown that the linked serotonin-2A receptor (5-HT(2A)R) A-1438 G and T102C polymorphisms modulate PPI in schizophrenia patients. Moreover, it was shown that genetic variation in the catechol-O-methyltransferase (COMT) and the neuregulin-1 (NRG-1) proteins influences PPI in schizophrenia patients and healthy volunteers. Therefore, we aimed to replicate these results and investigated the impact of the related polymorphisms on PPI in healthy human volunteers. We analyzed the 5-HT(2A)R A-1438 G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessing startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers. Subjects homozygous for the 5-HT(2A)R T102C-T/A-1438 G-A allele showed increased PPI levels. In particular, male subjects with the COMT Met158Met-genotype also showed elevated PPI. The NRG-1 Arg38Gln genotype did not have a significant impact on PPI. Startle reactivity was not affected by any of the investigated polymorphisms. We confirmed in an independent sample of healthy volunteers that PPI is influenced by genetic variation in the 5-HT(2A)R gene. The influence of the COMT Val158Met genotype on PPI appears to be sex-specific. These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 340 | Biochemistry 2009 Jul 48: 6450-60 |
| PMID | 19435324 |
| Title | A hotspot of inactivation: The A22S and V108M polymorphisms individually destabilize the active site structure of catechol O-methyltransferase. |
| Abstract | Human catechol O-methyltransferase (COMT) contains three common polymorphisms (A22S, A52T, and V108M), two of which (A22S and V108M) render the protein susceptible to deactivation by temperature or oxidation. We have performed multiple molecular dynamics simulations of the wild-type, A22S, A52T, and V108M COMT proteins to explore the structural consequences of these mutations. In total, we have amassed more than 1.4 micros of simulation time, representing the largest set of simulations detailing the effects of polymorphisms on a protein system to date. The A52T mutation had no significant effect on COMT structure in accord with experiment, thereby serving as a good negative control for the simulation set. Residues 22 (alpha2) and 108 (alpha5) interact with each other throughout the simulations and are located in a polymorphic hotspot approximately 20 A from the active site. Introduction of either the larger Ser (22) or Met (108) tightens this interaction, pulling alpha2 and alpha5 toward each other and away from the protein core. The V108M polymorphism rearranges active-site residues in alpha5, beta3, and alpha6, increasing the S-adenosylmethionine site solvent exposure. The A22S mutation reorients alpha2, moving critical catechol-binding residues away from the substrate-binding pocket. The A22S and V108M polymorphisms evolved independently in Northern European and Asian populations. While the decreased activities of both A22S and V108M COMT are associated with an increased risk for schizophrenia, the V108M-induced destabilization is also linked with improved cognitive function. These results suggest that polymorphisms within this hotspot may have evolved to regulate COMT activity and that heterozygosity for either mutation may be advantageous. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 341 | PLoS ONE 2009 -1 4: e5495 |
| PMID | 19424500 |
| Title | Association between catechol-O-methyltrasferase Val108/158Met genotype and prefrontal hemodynamic response in schizophrenia. |
| Abstract | "Imaging genetics" studies have shown that brain function by neuroimaging is a sensitive intermediate phenotype that bridges the gap between genes and psychiatric conditions. Although the evidence of association between functional val108/158met polymorphism of the catechol-O-methyltransferase gene (COMT) and increasing risk for developing schizophrenia from genetic association studies remains to be elucidated, one of the most topical findings from imaging genetics studies is the association between COMT genotype and prefrontal function in schizophrenia. The next important step in the translational approach is to establish a useful neuroimaging tool in clinical settings that is sensitive to COMT variation, so that the clinician could use the index to predict clinical response such as improvement in cognitive dysfunction by medication. Here, we investigated spatiotemporal characteristics of the association between prefrontal hemodynamic activation and the COMT genotype using a noninvasive neuroimaging technique, near-infrared spectroscopy (NIRS). Study participants included 45 patients with schizophrenia and 60 healthy controls matched for age and gender. Signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions from 52-channel NIRS and compared between two COMT genotype subgroups (Met carriers and Val/Val individuals) matched for age, gender, premorbid IQ, and task performance. The [oxy-Hb] increase in the Met carriers during the verbal fluency task was significantly greater than that in the Val/Val individuals in the frontopolar prefrontal cortex of patients with schizophrenia, although neither medication nor clinical symptoms differed significantly between the two subgroups. These differences were not found to be significant in healthy controls. These data suggest that the prefrontal NIRS signals can noninvasively detect the impact of COMT variation in patients with schizophrenia. NIRS may be a promising candidate translational approach in psychiatric neuroimaging. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 342 | J. Formos. Med. Assoc. 2009 Apr 108: 301-9 |
| PMID | 19369177 |
| Title | Association of the 3' region of COMT with schizophrenia in Taiwan. |
| Abstract | The Val108/158Met (rs4680) single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene contributes to genetic susceptibility to schizophrenia, which is specifically related to impairments in executive functioning. A different genomic region composed of three SNPs (rs737865, rs4680, rs165599) within the COMT gene has been reported to be significantly associated with schizophrenia in Ashkenazi Jews. This study aims to clarify the association between these three SNPs and their haplotypes with schizophrenia and neurocognitive functioning, using both case-control and family-based designs. The case-control study included 124 schizophrenia patients and 112 healthy controls, while the family samples included 83 families with at least two affected siblings. The neurocognitive functioning was assessed by the Continuous Performance Test (CPT) and Wisconsin Card Sorting Test. The association analysis was performed using TRANSMIT and FBAT. There was no significant association between the three SNPs and schizophrenia in the case-control study. In the family study, the A allele of rs165599 was transmitted preferentially to the affected individuals (p = 0.023), and significantly associated with a later age of onset (p = 0.018), more severe delusion/hallucination symptom dimension (p = 0.027), and poorer performance in the CPT (p = 0.04). The triple SNP haplotypes did not reveal any significant association with schizophrenia or neurocognitive function. The SNP rs165599, which has been mapped to the 3'-UTR region of the COMT gene, was significantly associated with schizophrenia in our family study, and possibly associated with the age of onset, delusion/hallucination symptom dimension, and CPT performance. Therefore, COMT may contribute to the genetic risk for schizophrenia not through the Val108/158Met polymorphism, but through other variants that are situated 3' to this region, in the Taiwanese population. Nevertheless, the true associated functional variants in our subjects remain to be elucidated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 343 | Rev Psiquiatr Salud Ment 2009 Apr 2: 89-94 |
| PMID | 23034243 |
| Title | Variability in the COMT gene and modification of the risk of schizophrenia conferred by cannabis consumption. |
| Abstract | The risk of schizophrenia conferred by cannabis has recently been proposed to be modulated by the Val158Met polymorphism (rs4680) at the COMT gene. To date, these findings have not been replicated in independent samples. We tested the potential gene-by-environment interaction between Val158Met genotype at the COMT gene and previous use of cannabis in schizophrenia in 192 healthy controls and 91 inpatients with DSM-IV schizophrenia. The functional COMT Val158Met polymorphism was analyzed using TaqMan technology. Cannabis use was measured by taking into account the frequency of intake during the previous month. Logistic regression models were used to test the interaction between genetic and environment factors. Cannabis use was strongly associated with the case condition (p<0.0001). The Val158Met polymorphism at the COMT gene was not associated with schizophrenia, although Val/Val homozygosity tended to be more frequent in the case group than in the control group (34% vs 27%; OR=1.39; 95% CI, 0.78-2.47). Finally, in women we found a non-significant trend toward the association when we tested for the interaction between cannabis use, the number of Val alleles and susceptibility to schizophrenia (p=0.152). Our results tend to support recent findings suggesting that the Val158Met polymorphism at the COMT gene modifies the risk of schizophrenia conferred by cannabis use. In our study, this possible effect was only detected in women. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 344 | Schizophr. Res. 2009 May 110: 140-8 |
| PMID | 19329282 |
| Title | Meta-analysis of association between genetic variants in COMT and schizophrenia: an update. |
| Abstract | A common functional polymorphism, Val108/158Met (rs4680), and haplotypes rs737865-rs4680-rs165599 in the Catechol-O-methyltransferase gene (COMT) have been extensively examined for association to schizophrenia; however, results of replication studies have been inconsistent. The aim of this study was to comprehensively evaluate the genetic risk of COMT for schizophrenia. First, we performed a mutation scan to detect the existence of potent functional variants in the 5'-flanking and exon regions. Second, we conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) in COMT [19 SNPs including six possible functional SNPs (rs2075507, rs737865, rs4680, rs165599, rs165849)] and schizophrenia in large Japanese samples (schizophrenics 1118, controls 1100). Lastly, we carried out a meta-analysis of 5 functional SNPs and haplotypes (rs737865-rs4680-rs165599). No novel functional variant was detected in the mutation scan. There is no association between these tagging SNPs in COMT and Japanese schizophrenia. In this updated meta-analysis, no evidence was found for an association between Val108/158Met polymorphisms, rs6267, rs165599, and haplotypes (rs7378655-rs4680-rs165599) and schizophrenia, although rs2075507 and rs737865 showed trends for significance in allele-wise analyses (P=0.039 in a multiplicative model, P=0.025 in a recessive model for rs2075507, P=0.018 in a dominant model for rs737865, uncorrected). This significance did not remain, however, after correcting the P-values using a false discovery rate controlling procedure. Our results suggest that the COMT is unlikely to contribute to susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 345 | Pharmacogenomics 2009 Mar 10: 385-97 |
| PMID | 19290789 |
| Title | Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. |
| Abstract | We investigated the catechol-O-methyltrasferase (COMT) gene, which is a strong functional and positional candidate gene for schizophrenia and therapeutic response to antipsychotic medication. Single-locus as well as detailed haplotype-based association analysis of the COMT gene with schizophrenia and antipsychotic treatment response was carried out using seven COMT polymorphisms in 398 schizophrenia patients and 241 healthy individuals from a homogeneous south Indian population. Further responsiveness to risperidone treatment was assessed in 117 schizophrenia patients using Clinical Global Impressions (CGI). A total of 69 patients with a CGI score of 2 or less met the criteria of good responders and 48 were patients who continued to have a score of 3 and above and were classified as poor responders to risperidone treatment. The association of SNP rs4680 with schizophrenia did not remain significant after adjusting for multiple testing. Haplotype analysis showed highly significant association of seven COMT marker haplotypes with schizophrenia (CLUMP T4 p-value = 0.0001). Our results also demonstrated initial significant allelic associations of two SNPs with drug response (rs4633: chi(2) = 4.36, p-value = 0.036, OR: 1.80, 95% CI: 1.03-3.15; and rs4680: chi(2) = 4.02, p-value = 0.044, OR: 1.76, 95% CI: 1.01-3.06) before multiple correction. We employed two-marker sliding window analysis for haplotype association and observed a significant association of markers located between intron 1 and intron 2 (rs737865, rs6269: CLUMP T4 p-value = 0.021); and in exon 4 (rs4818, rs4680: CLUMP T4 p-value = 0.028) with drug response. The present study thus indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients. However, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 346 | J. Neurogenet. 2009 -1 23: 341-52 |
| PMID | 19225952 |
| Title | Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip). |
| Abstract | It has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 347 | Genes Brain Behav. 2009 Mar 8: 228-37 |
| PMID | 19077118 |
| Title | Genetic variants in COMT and neurocognitive impairment in families of patients with schizophrenia. |
| Abstract | This study examined the relations of genetic variants in catechol-O-methyltransferase (COMT) gene, including rs737865 in intron 1, rs4680 in exon 4 (Val158Met) and downstream rs165599, to schizophrenia and its related neurocognitive functions in families of patients with schizophrenia. Totally, 680 individuals from 166 simplex (166 affected members and 354 nonpsychotic first-degree relatives) and 46 multiplex families (85 affected members and 75 nonpsychotic first-degree relatives) were interviewed using Diagnostic Interview for Genetic Studies, administered Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT), and drawn for venous blood. Both categorical (dichotomizing families on affected members' neurocognitive performance) and quantitative approaches toward the WCST and CPT performance scores were employed using the family-based association test and the variance components framework, respectively. Both false discovery rate and permutations were used to adjust for multiple testing. The genotypes of rs4680 were associated with both the WCST and CPT performance scores in these families, but not with schizophrenia per se in either whole sample or subgroup analyses. Meanwhile, the other two single nucleotide polymorphisms were differentially associated with the two tasks. For WCST indexes, regardless of subgroup analyses or quantitative approach, only rs737865 exhibited moderate associations. For CPT indexes, rs737865 exhibited association for the subgroup with deficit on CPT reaction time, whereas rs165599 exhibited association for the subgroup with deficit on CPT d' as well as quantitative undegraded d'. Our results indicate that the genetic variants in COMT might be involved in modulation of neurocognitive functions and hence conferring increased risk to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 348 | Neuroimage 2009 Mar 45: 44-51 |
| PMID | 19071221 |
| Title | Impact of interacting functional variants in COMT on regional gray matter volume in human brain. |
| Abstract | Functional variants in the catechol-O-methyltransferase (COMT) gene have been shown to impact cognitive function, cortical physiology and risk for schizophrenia. A recent study showed that previously reported effects of the functional val158met SNP (rs4680) on brain function are modified by other functional SNPs and haplotypes in the gene, though it was unknown if these effects are also seen in brain structure. We used voxel-based morphometry to investigate the impact of multiple functional variants in COMT on gray matter volume in a large group of 151 healthy volunteers from the CBDB/NIMH Genetic Study of schizophrenia. We found that the previously described rs4680 val risk variant affects hippocampal and dorsolateral prefrontal (DLPFC) gray matter volume. In addition, we found that this SNP interacts with a variant in the P2 promoter region (rs2097603) in predicting changes in hippocampal gray matter volume consistent with a nonlinear effect of extracellular dopamine. We report evidence that interacting functional variants in COMT affect gray matter regional volume in hippocampus and DLPFC, providing further in vivo validation of the biological impact of complex genetic variation in COMT on neural systems relevant for the pathophysiology of schizophrenia and extending observations of nonlinear dependence of prefrontal neurons on extracellular dopamine to the domain of human brain structure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 349 | Biol. Psychiatry 2009 Mar 65: 473-80 |
| PMID | 19054502 |
| Title | Opposite effects of catechol-O-methyltransferase Val158Met on cortical function in healthy subjects and patients with schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) is essential for dopamine metabolism in the brain, and normal variation in the COMT Val158Met polymorphism can influence regional brain function during cognitive tasks. How this is affected when central dopamine function is perturbed is unclear. We addressed this by comparing the effects of COMT Val158Met genotype on cortical activation during a task of executive functions in healthy and schizophrenic subjects. We studied 90 subjects comprising 48 healthy volunteers (15 Met158/Met158, 20 Val158/Met158, and 13 Val158/Val158) and 42 patients with DSM-IV schizophrenia (13 Met158/Met158, 17 Val158/Met158, and 12 Val158/Val158). Subjects were studied with functional magnetic resonance imaging while performing a verbal fluency task, with performance recorded online. Main effects of genotype and diagnosis and their interaction on cortical activation and functional connectivity were assessed using SPM5. In the right peri-Sylvian cortex, the Met158 allele of the COMT Val158Met polymorphism was associated with greater activation than the Val158 allele in control subjects; the converse applied in patients (Z = 4.3; false discovery rate p = .04). There was also a strong trend for a group x genotype interaction on functional connectivity between this right peri-Sylvian region and the left anterior insula/operculum (Z = 3.4; p < .001, uncorrected). These findings were independent of between-group differences in task performance, medication, demographic factors, or IQ. Frontotemporal function during verbal generation is modulated by variation in COMT genotype. This effect is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 350 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Mar 150B: 282-9 |
| PMID | 18553389 |
| Title | Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia. |
| Abstract | Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 351 | Schizophr Bull 2009 Jul 35: 826-39 |
| PMID | 18381357 |
| Title | Genetic and disorder-specific aspects of resting state EEG abnormalities in schizophrenia. |
| Abstract | We evaluated whether abnormal frequency composition of the resting state electroencephalogram (EEG) in schizophrenia was associated with genetic liability for the disorder by studying first-degree biological relatives of schizophrenia patients. The study included a data-driven method for defining EEG frequency components and determined the specificity of resting state EEG frequency abnormalities by assessing schizophrenia patients, bipolar disorder patients, and relatives of both patient groups. schizophrenia patients and their relatives, but not bipolar patients or their relatives, exhibited increased high-frequency activity (beta) providing evidence for disturbances in resting state brain activity being specific to genetic liability for schizophrenia. schizophrenia patients exhibited augmented low-frequency EEG activity (delta, theta), while bipolar disorder patients and the 2 groups of relatives generally failed to manifest similar low-frequency EEG abnormalities. The Val(158)Met polymorphism for the catechol-O-methyl transferase (COMT) gene was most strongly associated with delta and theta activity in schizophrenia patients. Met homozygote schizophrenia patients exhibited augmented activity for the 2 low-frequency bands compared with control subjects. Excessive high-frequency EEG activity over frontal brain regions may serve as an endophenotype that reflects cortical expression of genetic vulnerability for schizophrenia. Low-frequency resting state EEG anomalies in schizophrenia may relate to disorder-specific pathophysiology in schizophrenia and the influence of the COMT gene on tonic dopamanergic function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 352 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 353 | J. Hum. Genet. 2009 Dec 54: 709-12 |
| PMID | 19881467 |
| Title | Association analysis of COMT polymorphisms with schizophrenia and smooth pursuit eye movement abnormality. |
| Abstract | schizophrenia is a multifactorial disorder characterized by the contribution of multiple susceptibility genes that may act in conjunction with epigenetic processes and environmental factors. The catechol-O-methyltransferase (COMT) gene, which is located in the 22q11 microdeletion, has been considered as a candidate gene for schizophrenia because of its ability to degrade catecholamines, including dopamine. In a genetic analysis, neurophysiological endophenotype in schizophrenia, such as smooth pursuit eye movement (SPEM) disturbance, is considered to be a good trait marker, because it may be under more direct genetic control. This study was performed to examine the genetic association of COMT polymorphisms with the risk of schizophrenia and SPEM abnormality in a Korean population. Six single-nucleotide polymorphisms of COMT were genotyped by TaqMan assay. Their genetic effects on the risk of schizophrenia were analyzed in 354 patients and 396 controls using chi(2) analyses. Among the schizophrenic patients, 166 subjects were selected for association analyses of COMT polymorphisms with SPEM abnormality. From the six COMT polymorphisms, rs6267 showed an association with the reduced risk of schizophrenia after correction (P(corr) = 0.02). In analysis of SPEM abnormality, no significant associations were detected with COMT polymorphisms. The results of the present study provide the evidence that in a Korean population, COMT on the 22q11 locus is likely involved in the development of schizophrenia, but not in the SPEM function abnormality. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 354 | Med. Sci. Monit. 2009 Sep 15: CR484-9 |
| PMID | 19721400 |
| Title | Association between COMT gene and Chinese male schizophrenic patients with violent behavior. |
| Abstract | Haplotype analysis is hypothesized as having better power than individual SNPs in detecting the association between genotype and phenotype, but this approach has rarely been used in studies of the genetics of violent behavior in schizophrenia. The aim of this study was to further examine the role of the COMT gene in violent behavior. Both individual SNP and haplotype were used to explore associations between COMT polymorphisms and violent behavior in 252 patients with violent behavior and 332 patients without violent behavior of Chinese Han schizophrenics. Then the association between a three-marker haplotype (SNPs rs4680, rs737865, and rs165599) and violent behavior was explored by performing haplotype analysis using SHEsis and PHASE. Finally, the Modified Overt Aggression Scale (MOAS) was used to assess the aggressive or violent behaviors of the patients. No association was found between the individual SNPs and violent behavior in schizophrenia. However, an association was found between haplotypes and violent behavior. The frequency of the haplotype A-A-G was higher in the case group and that of haplotype G-G-A was higher in the control group. Furthermore, the patients with haplotype A-A-G scored higher on the "physical aggression against objects" subscale of the MOAS than those with the haplotype G-G-A in the case group. There is an association between COMT gene and violent behavior in Chinese schizophrenics. The haplotypes A-A-G and G-G-A may be used to predict violent behavior in Chinese schizophrenics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 355 | Pharmacopsychiatry 2009 Jul 42: 141-4 |
| PMID | 19585392 |
| Title | COMT Val 158 Met polymorphism is associated with cognitive flexibility in a signal discrimination task in schizophrenia. |
| Abstract | Associations between the well-known functional single nucleotide polymorphism Val (158)Met in the gene encoding catechol- O-methyltransferase (COMT) and cognitive do-mains affected in schizophrenia are inconsistent regarding directionality and specific impact and call for a more fundamental cognitive endophenotype. Recent studies suggest that the COMT genotype contributes to cognitive flexibility, a fundamental cognitive ability that potentially influences an individual's performance in a variety of other neurocognitive tasks. We investigated the association between COMT Val (158)Met genotype and cognitive flexibility as assessed by signal discrimination in the Continuous Performance Test - Identical Pairs version in a cohort of 111 German schizophrenic patients. COMT genotype was significantly associated with signal discrimination index d' in schizophrenia. The Val/Val genotype was associated with the highest and the Met/Met genotype with the lowest scores; heterozygous individuals displayed an intermediate performance. Our data suggest that allelic variation at the COMT Val (158)Met locus may influence signal discrimination capacity in schizophrenia and confirm that Val loading, probably due to decreased prefrontal dopamine availability, is associated with greater cognitive flexibility, which in turn may influence other cognitive measures that have been associated with COMT to date. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 356 | Biol. Psychiatry 2009 Jun 65: 1048-54 |
| PMID | 19159868 |
| Title | Evidence of epistasis between the catechol-O-methyltransferase and aldehyde dehydrogenase 3B1 genes in paranoid schizophrenia. |
| Abstract | schizophrenia is a common yet severe psychiatric condition characterized by complex genetic mechanism and diverse clinical presentations. Our previous study indicated that the combined effect of two intronic single nucleotide polymorphisms (SNPs), which are located in the catechol-O-methyltransferase (COMT) and aldehyde dehydrogenase 3B1 (ALDH3B1) genes, respectively, conferred genetic risk to paranoid schizophrenia. To further explore the precise mechanism of the COMT and ALDH3B1 interaction involved in the pathophysiology of schizophrenia, we scanned all possible functional SNPs within these two genes by polymerase chain reaction (PCR)-based genotyping analysis in 540 paranoid schizophrenic patients and 660 control subjects from a Han Chinese population. We also determined the effects of schizophrenia-associated SNPs on the development of psychotic symptoms, P300 event-related potential components induced by an auditory odd-ball task, and gene expression examined by quantitative real-time PCR analysis. The major findings of this study were that, among the individuals carrying the rs3751082 A allele in the ALDH3B1 gene, the rs4633 T allele in the COMT gene was associated with susceptibility to paranoid schizophrenia (p = .004), development of hallucination (p = 5.141 E-5), delay of P300 latency in both patients (p = .006) and control subjects (p = .02), and increased expression of the COMT gene in control subjects (p = .002). However, the rs4633 T allele did not show any association in the rs3751082 G/G genotype carriers. These findings provided convincing evidence that epistasis between the COMT and ALDH3B1 genes plays an important role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 357 | Med. Sci. Monit. 2009 Sep 15: CR484-9 |
| PMID | 19721400 |
| Title | Association between COMT gene and Chinese male schizophrenic patients with violent behavior. |
| Abstract | Haplotype analysis is hypothesized as having better power than individual SNPs in detecting the association between genotype and phenotype, but this approach has rarely been used in studies of the genetics of violent behavior in schizophrenia. The aim of this study was to further examine the role of the COMT gene in violent behavior. Both individual SNP and haplotype were used to explore associations between COMT polymorphisms and violent behavior in 252 patients with violent behavior and 332 patients without violent behavior of Chinese Han schizophrenics. Then the association between a three-marker haplotype (SNPs rs4680, rs737865, and rs165599) and violent behavior was explored by performing haplotype analysis using SHEsis and PHASE. Finally, the Modified Overt Aggression Scale (MOAS) was used to assess the aggressive or violent behaviors of the patients. No association was found between the individual SNPs and violent behavior in schizophrenia. However, an association was found between haplotypes and violent behavior. The frequency of the haplotype A-A-G was higher in the case group and that of haplotype G-G-A was higher in the control group. Furthermore, the patients with haplotype A-A-G scored higher on the "physical aggression against objects" subscale of the MOAS than those with the haplotype G-G-A in the case group. There is an association between COMT gene and violent behavior in Chinese schizophrenics. The haplotypes A-A-G and G-G-A may be used to predict violent behavior in Chinese schizophrenics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 358 | Schizophr. Res. 2009 May 110: 140-8 |
| PMID | 19329282 |
| Title | Meta-analysis of association between genetic variants in COMT and schizophrenia: an update. |
| Abstract | A common functional polymorphism, Val108/158Met (rs4680), and haplotypes rs737865-rs4680-rs165599 in the Catechol-O-methyltransferase gene (COMT) have been extensively examined for association to schizophrenia; however, results of replication studies have been inconsistent. The aim of this study was to comprehensively evaluate the genetic risk of COMT for schizophrenia. First, we performed a mutation scan to detect the existence of potent functional variants in the 5'-flanking and exon regions. Second, we conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) in COMT [19 SNPs including six possible functional SNPs (rs2075507, rs737865, rs4680, rs165599, rs165849)] and schizophrenia in large Japanese samples (schizophrenics 1118, controls 1100). Lastly, we carried out a meta-analysis of 5 functional SNPs and haplotypes (rs737865-rs4680-rs165599). No novel functional variant was detected in the mutation scan. There is no association between these tagging SNPs in COMT and Japanese schizophrenia. In this updated meta-analysis, no evidence was found for an association between Val108/158Met polymorphisms, rs6267, rs165599, and haplotypes (rs7378655-rs4680-rs165599) and schizophrenia, although rs2075507 and rs737865 showed trends for significance in allele-wise analyses (P=0.039 in a multiplicative model, P=0.025 in a recessive model for rs2075507, P=0.018 in a dominant model for rs737865, uncorrected). This significance did not remain, however, after correcting the P-values using a false discovery rate controlling procedure. Our results suggest that the COMT is unlikely to contribute to susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 359 | Biol. Psychiatry 2009 Mar 65: 473-80 |
| PMID | 19054502 |
| Title | Opposite effects of catechol-O-methyltransferase Val158Met on cortical function in healthy subjects and patients with schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) is essential for dopamine metabolism in the brain, and normal variation in the COMT Val158Met polymorphism can influence regional brain function during cognitive tasks. How this is affected when central dopamine function is perturbed is unclear. We addressed this by comparing the effects of COMT Val158Met genotype on cortical activation during a task of executive functions in healthy and schizophrenic subjects. We studied 90 subjects comprising 48 healthy volunteers (15 Met158/Met158, 20 Val158/Met158, and 13 Val158/Val158) and 42 patients with DSM-IV schizophrenia (13 Met158/Met158, 17 Val158/Met158, and 12 Val158/Val158). Subjects were studied with functional magnetic resonance imaging while performing a verbal fluency task, with performance recorded online. Main effects of genotype and diagnosis and their interaction on cortical activation and functional connectivity were assessed using SPM5. In the right peri-Sylvian cortex, the Met158 allele of the COMT Val158Met polymorphism was associated with greater activation than the Val158 allele in control subjects; the converse applied in patients (Z = 4.3; false discovery rate p = .04). There was also a strong trend for a group x genotype interaction on functional connectivity between this right peri-Sylvian region and the left anterior insula/operculum (Z = 3.4; p < .001, uncorrected). These findings were independent of between-group differences in task performance, medication, demographic factors, or IQ. Frontotemporal function during verbal generation is modulated by variation in COMT genotype. This effect is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 360 | Psychiatry Res 2010 Mar 176: 94-5 |
| PMID | 20053459 |
| Title | Interaction of catechol-O-methyltransferase (COMT) Val108/158 Met genotype and risperidone treatment in Chinese Han patients with schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 361 | Dialogues Clin Neurosci 2010 -1 12: 449-56 |
| PMID | 21319490 |
| Title | Imaging genetics of schizophrenia. |
| Abstract | Recent years have seen an explosive growth of interest in the application of imaging genetics to understand neurogenetic mechanisms of schizophrenia. Imaging genetics applies structural and functional neuroimaging to study subjects carrying genetic risk variants that relate to a psychiatric disorder. We review selected aspects of this literature, starting with a widely studied candidate gene--the catechol-O-methyltransferase gene (COMT)--discussing other candidate genes in the dopaminergic system, and then discussing variants with genome-wide support. In future perspectives, approaches to characterize epistatic effects, the identification of new risk genes through forward-genetic approaches using imaging phenotypes, and the study of rare structural variants are considered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 362 | Epidemiol Health 2010 -1 32: e2010011 |
| PMID | 21217836 |
| Title | No Association Between Functional Polymorphisms in COMT and MTHFR and Schizophrenia Risk in Korean Population. |
| Abstract | Common genetic SNPs in two genes, encoding catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR), which are interconnected with COMT gene regulation, have been reported to contribute to schizophrenia risk. In this study, we evaluated the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk with a case-control study in a Korean population. We performed a case-control study by genotyping analysis using 360 cases and 348 controls in Korean subjects to determine the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk. Four functional SNPs in COMT (Val158Met and rs165599) and MTHFR (C677T and A1298C) were genotyped by primer extension assay. None of the genotype distributions for the four SNPs was significantly different between cases and controls. Stratified analysis did not show any significant gender difference for any polymorphism. In addition, we found no evidence of a gene-gene interaction in the analysis of combined genotypes. Our results suggest no significant association between the selected functional polymorphisms of COMT or MTHFR in Korean schizophrenia subjects. However, further studies are required to confirm our findings in a larger number of subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 363 | Schizophr. Res. 2010 Sep 122: 24-30 |
| PMID | 20643532 |
| Title | The catechol-O-methyl transferase (COMT) gene and its potential association with schizophrenia: findings from a large German case-control and family-based sample. |
| Abstract | The aim of the present study was to investigate possible associations between schizophrenia and 13 SNP markers in COMT. No association was observed in 631 cases, 207 nuclear families, and 776 controls. A cognitive performance phenotype (Trail Marking Test) was available for a subgroup of the patients. No association was found between the 13 markers and this phenotype. Four clinically-defined subgroups (early age at onset, negative symptoms, family history of schizophrenia, and life-time major depressive episode) were also investigated. Associations were observed for 3 of these subgroups, although none withstood correction for multiple testing. COMT does not appear to be a risk factor for schizophrenia in this population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 364 | Eur. Psychiatry 2010 Oct 25: 320-2 |
| PMID | 20570494 |
| Title | COMT Val 158 Met polymorphism is related with interpersonal problem solving in schizophrenia. |
| Abstract | The aim of this study was to investigate associations between COMT Val(158)Met polymorphism, and interpersonal problem solving capacity and cognitive functions in schizophrenia. COMT Val(158)Met polymorphism was studied with ARMS-PCR method in 99 outpatients with schizophrenia. Brief Psychiatric Rating Scale was used to assess symptom severity. The Assessment of Interpersonal Problem Solving Skills (AIPSS) was used to evaluate problem solving capacity. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST), were used to measure cognition. Patients with Met/Met genotype had higher AIPSS subscores for detecting the problem, than those with Val/Val at baseline (p=0.02). Met allele was also found to be related with higher AIPSS-receiving skills (p=0.04). Val allele was found to be related with more commission errors in CPT (p=0.03). There was no relation between Val(158)Met polymorphism and WCST and clinical measurements. Our findings suggest that Val allele might be related to poor performance on detecting the interpersonal problems, and attention in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 365 | Psychiatr Danub 2010 Jun 22: 270-4 |
| PMID | 20562760 |
| Title | Catechol-O-methyl transferase and schizophrenia. |
| Abstract | Catechol-O-methyl transferase (COMT) is an enzyme involved in the degradation of dopamine. The most commonly examined polymorphism within the COMT gene is Val108/158Met polymorphism, which results in three to fourfold difference in COMT enzyme activity. It is particularely important in prefrontal cortex, since COMT activity is the most important regulator of the prefrontal dopamine function. Given the association between schizophrenia and decreased dopamine activity in the prefrontal cortex, it is not surprising that Val108/158Met polymorphism is among the most extensively investigated polymorphisms in schizophrenia. According to different studies, Val allele may be a small risk factor for schizophrenia. There is also some evidence that Val108/158Met polymorphism influences the age of onset of schizophrenia, cognitive function, severity of psychotic symptoms, as well as efficacy and adverse events of antipsychotics. Heterogenity of patient population has undoubtedly influenced the results of these studies. Interaction of Val108/158Met polymorphism with other genes and environmental factors is an important avenue for future research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 366 | Brain Res. 2010 Aug 1348: 114-9 |
| PMID | 20561508 |
| Title | Disruption of thermal nociceptive behaviour in mice mutant for the schizophrenia-associated genes NRG1, COMT and DISC1. |
| Abstract | Abnormalities in pain perception, especially altered warmth and heat pain sensitivity, have been reported in schizophrenia. Therefore, genes associated with schizophrenia, including neuregulin-1 (NRG1), catechol-O-methyltranferase (COMT) and disrupted-in-schizophrenia-1 (DISC1), may play a role in modulating the physiological and psychological effects of pain stimuli in such patients. Thermal pain sensitivity was assessed in NRG1, COMT and DISC1 mutant mice, and the anti-nociceptive effects of acute Delta(9)-tetrahydrocannabinol (THC) were compared in NRG1 and COMT mutants. At baseline, deletion of NRG1 and DISC1 each reduced thermal pain sensitivity, while deletion of COMT increased pain sensitivity. Neither NRG1 nor COMT deletion altered the anti-nociceptive effects of acute systemic THC (8.0mg/kg). These results indicate a differential contribution of NRG1 and DISC1 vis-à-vis COMT to the processing of thermal nociceptive stimuli and extend their phenotypic relationship to psychotic illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 367 | Psychiatry Res 2010 Sep 179: 147-50 |
| PMID | 20483479 |
| Title | Analysis of association between the catechol-O-methyltransferase (COMT) gene and negative symptoms in chronic schizophrenia. |
| Abstract | Negative symptoms commonly seen in chronic schizophrenia are related to prefrontal hypodopaminergia. Dysfunction of the catechol-O-methyltransferase (COMT) gene has long been thought to confer susceptibility to schizophrenia because of its catalytic activity for dopamine degradation. The present study is an attempt to perform a quantitative trait test for genetic association between the COMT gene and negative symptoms in a Chinese population. A total of 290 unrelated individuals with schizophrenia patients were recruited and their symptoms were assessed through the Positive and Negative Syndrome Scale (PANSS). The quantitative trait test was performed by the UNPHASED programme to examine the correlation between the scored negative symptoms and the coding single nucleotide polymorphisms (SNPs) present in the COMT gene. The rs4633-rs4680 haplotype showed significant association with the overall score of negative symptoms, and four individual negative symptoms, including blunted affect, emotional withdrawal, poor rapport and passive/apathetic social withdrawal. SNP rs4680 (Val/Met) showed significant association with blunted affect. The present finding suggests that the COMT gene may a etiologically contribute to the severity of negative symptoms in schizophrenia, but its precise mechanism needs further investigating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 368 | Neuroimage 2010 Nov 53: 899-907 |
| PMID | 20398774 |
| Title | COMT Val158Met polymorphism in relation to activation and de-activation in the prefrontal cortex: A study in patients with schizophrenia and healthy subjects. |
| Abstract | The Val158Met polymorphism in the COMT gene has been found to be associated with differences in brain activation in both healthy subjects and patients with schizophrenia. The predominant finding has been increased prefrontal activation associated with the Val allele; however, genotype-related de-activations have not been studied. In this study 42 schizophrenia patients and 31 controls underwent fMRI while performing the n-back task. Brain differences related to presence/absence of disease and presence/absence of the Val/Val genotype were examined. Both disease and Val/Val genotype were associated with failure of de-activation in a cluster centred in the medial prefrontal cortex. There was no interaction between disease and genotype at this location, but clusters where there were significant interactions emerged in the right prefrontal cortex and left temporal/parietal cortex. These findings suggest that Val158Met polymorphism influences task-related de-activations in the default mode network in both healthy subjects and schizophrenia patients to an equivalent extent. However the Val158Met polymorphism also has disease-specific effects on DLPFC activation in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 369 | Schizophr Bull 2010 Mar 36: 341-6 |
| PMID | 18635674 |
| Title | Sensorimotor gating of schizophrenia patients depends on Catechol O-methyltransferase Val158Met polymorphism. |
| Abstract | It has been recently shown that Catechol O-methyltransferase (COMT) Val(158)Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val(158)Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val(158)Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val(158)Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val(158)Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 370 | PLoS ONE 2010 -1 5: e10789 |
| PMID | 20520724 |
| Title | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| Abstract | Neuregulin1 (NRG1)-ErbB signaling has been implicated in the pathogenesis of cancer and schizophrenia. We have previously reported that NRG1-stimulated migration of B lymphoblasts is PI3K-AKT1dependent and impaired in patients with schizophrenia and significantly linked to the catechol-o-methyltransferase (COMT) Val108/158Met functional polymorphism. We have now examined AKT1 activation in NRG1-stimulated B lymphoblasts and other cell models and explored a functional relationship between COMT and AKT1. NRG1-induced AKT1 phosphorylation was significantly diminished in Val carriers compared to Met carriers in both normal subjects and in patients. Further, there was a significant epistatic interaction between a putatively functional coding SNP in AKT1 (rs1130233) and COMT Val108/158Met genotype on AKT1 phosphorylation. NRG1 induced translocation of AKT1 to the plasma membrane also was impaired in Val carriers, while PIP(3) levels were not decreased. Interestingly, the level of COMT enzyme activity was inversely correlated with the cells' ability to synthesize phosphatidylserine (PS), a factor that attracts the pleckstrin homology domain (PHD) of AKT1 to the cell membrane. Transfection of SH-SY5Y cells with a COMT Val construct increased COMT activity and significantly decreased PS levels as well as NRG1-induced AKT1 phosphorylation and migration. Administration of S-adenosylmethionine (SAM) rescued all of these deficits. These data suggest that AKT1 function is influenced by COMT enzyme activity through competition with PS synthesis for SAM, which in turn dictates AKT1-dependent cellular responses to NRG1-mediated signaling. Our findings implicate genetic and functional interactions between COMT and AKT1 and may provide novel insights into pathogenesis of schizophrenia and other ErbB-associated human diseases such as cancer. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 371 | Int. J. Neuropsychopharmacol. 2010 Sep 13: 981-96 |
| PMID | 20219156 |
| Title | Cognitive impairment following prenatal immune challenge in mice correlates with prefrontal cortical AKT1 deficiency. |
| Abstract | Accumulating evidence indicates that genetically determined deficiency in the expression of the cytoplasmic serine-threonine protein kinase AKT1 may contribute to abnormal prefrontal cortical structure and function relevant to the cognitive disturbances in schizophrenia. However, it remains essentially unknown whether prefrontal AKT1 expression may also be influenced by environmental factors implicated in the aetiology of this mental illness. One of the relevant environmental risk factors of schizophrenia and related disorders is prenatal exposure to infection and/or immune activation. This study therefore explored whether prenatal immune challenge may lead to prefrontal AKT1 deficiency and associated changes in cognitive functions attributed to the prefrontal cortex. For these purposes, we used a well-established experimental mouse model of prenatal exposure to a viral-like acute phase response induced by the synthetic analogue of double-stranded RNA, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that adult offspring born to PolyI:C-treated mothers showed delay-dependent impairments in spatial working memory and recognition memory together with a marked reduction of AKT1-positive cells in the prefrontal cortex. These effects emerged in the absence of concomitant changes in prefrontal catechol-O-methyltransferase (COMT) density. Correlative analyses further demonstrated a significant positive correlation between the number of AKT1-positive cells in distinct prefrontal cortical subregions and cognitive performance under high storage load in the temporal domain. Our findings thus highlight that schizophrenia-related alterations in AKT1 signalling and associated cognitive dysfunctions may not only be precipitated by genetically determined factors, but may also be produced by (immune-associated) environmental insults implicated in the aetiology of this disabling brain disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 372 | Behav Brain Funct 2010 -1 6: 67 |
| PMID | 21029471 |
| Title | Executive functions and selective attention are favored in middle-aged healthy women carriers of the Val/Val genotype of the catechol-o-methyltransferase gene: a behavioral genetic study. |
| Abstract | Cognitive deficits such as poor memory, the inability to concentrate, deficits in abstract reasoning, attention and set-shifting flexibility have been reported in middle-aged women. It has been suggested that cognitive decline may be due to several factors which include hormonal changes, individual differences, normal processes of aging and age-related changes in dopaminergic neurotransmission. Catechol-O-methyltransferase (COMT), a common functional polymorphism, has been related to executive performance in young healthy volunteers, old subjects and schizophrenia patients. The effect of this polymorphism on cognitive function in middle-aged healthy women is not well known. The aim of the current study was to investigate whether measures of executive function, sustained attention, selective attention and verbal fluency would be different depending on the COMT genotype and task demand. We genotyped 74 middle-aged healthy women (48 to 65 years old) for the COMT Val158Met polymorphism. We analyzed the effects of this polymorphism on executive functions (Wisconsin Card Sorting Test), selective attention (Stroop test), sustained attention (Continuous Performance Test) and word generation (Verbal Fluency test), which are cognitive functions that involve the frontal lobe. There were 27 women with the Val/Val COMT genotype, 15 with the Met/Met genotype, and 32 with the Val/Met genotype. Women carriers of the Val/Val genotype performed better in executive functions, as indicated by a lower number of errors committed in comparison with the Met/Met or Val/Met groups. The correct responses on selective attention were higher in the Val/Val group, and the number of errors committed was higher in the Met/Met group during the incongruence trial in comparison with the Val/Val group. Performance on sustained attention and the number of words generated did not show significant differences between the three genotypes. These findings indicate that middle-aged women carriers of the Val158 allele, associated with high-activity COMT, showed significant advantage over Met allele in executive processes and cognitive flexibility. These results may help to explain, at least in part, individual differences in cognitive decline in middle-aged women with dopamine-related genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 373 | Behav Brain Funct 2010 -1 6: 53 |
| PMID | 20836853 |
| Title | COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination. |
| Abstract | Dopamine in prefrontal cortex (PFC) modulates core cognitive processes, notably working memory and executive control. Dopamine regulating genes and polymorphisms affecting PFC--including Catechol-O-Methyltransferase (COMT) Val158Met--are crucial to understanding the molecular genetics of cognitive function and dysfunction. A mechanistic account of the COMT Val158Met effect associates the Met allele with increased tonic dopamine transmission underlying maintenance of relevant information, and the Val allele with increased phasic dopamine transmission underlying the flexibility of updating new information. Thus, consistent with some earlier work, we predicted that Val carriers would display poorer performance when the maintenance component was taxed, while Met carriers would be less efficient when rapid updating was required. Using a Stroop task that manipulated level of required cognitive stability and flexibility, we examined reaction time performance of patients with schizophrenia (n = 67) and healthy controls (n = 186) genotyped for the Val/Met variation. In both groups we found a Met advantage for tasks requiring cognitive stability, but no COMT effect when a moderate level of cognitive flexibility was required, or when a conflict cost measure was calculated. Our results do not support a simple stability/flexibility model of dopamine COMT Val/Met effects and suggest a somewhat different conceptualization and experimental operationalization of these cognitive components. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 374 | Schizophr. Res. 2010 Sep 122: 31-7 |
| PMID | 20605701 |
| Title | Catechol O-methyltransferase variants and cognitive performance in schizophrenia and bipolar disorder versus controls. |
| Abstract | The gene encoding Catechol O-methyltransferase (COMT), a dopamine catabolic enzyme, is an important candidate gene in several psychiatric disorders. Several studies have shown an association between the functional Val(158)Met polymorphism and cognitive performance. However, the results have been inconsistent and there are few studies addressing other COMT single nucleotide polymorphisms (SNPs). We investigated SNPs across the whole COMT gene, including the Val(158)Met polymorphism, for a putative effect on working memory, executive function and IQ in 315 patients with schizophrenia or bipolar disorder and 340 healthy controls. We replicated the association between the Val(158)Met variant and working memory performance, and found a significant interaction between this SNP and diagnosis, with patients with schizophrenia showing a specific, reduced performance on the 2-back test. Several other COMT SNPs were associated with different cognitive functions, but did not remain significant after controlling for multiple testing. We also found significant interaction effects between the SNP variants and gender. The present study replicates earlier findings showing an association between the functional Val(158)Met polymorphism and working memory performance, with schizophrenia subjects particularly vulnerable. Furthermore, our findings suggest that other parts of the COMT gene seem to affect several related cognitive domains, which further support the notion that COMT is a modifier gene in prefrontal dopamine functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 375 | World J. Biol. Psychiatry 2010 Sep 11: 803-12 |
| PMID | 20586531 |
| Title | The catechol-O-methyl-transferase gene in tardive dyskinesia. |
| Abstract | Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol-O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients (n=226; 196 Caucasians and 30 African Americans). We found a significant association between the marker rs165599 in the 3' untranslated region of COMT and TD (AA versus G-carrier: OR(AA)=2.22, 95% CI:1.23-4.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies (n=6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (OR(ValVal)=1.63, 95% CI: 1.09-2.45; P=0.019) but not in males. Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 376 | Psychiatry Res 2010 Oct 179: 291-6 |
| PMID | 20493536 |
| Title | Catechol-O-Methyltransferase (COMT) Val158Met variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications. |
| Abstract | New models of interaction between genetic and environmental factors have been proposed to explain the pathogenesis of schizophrenia. The Val158Met polymorphism of the COMT (Catechol-O-Methyltransferase) gene, involved in dopamine regulation and related to negative symptoms, has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The aim of the study was to explore the existence of an interaction between COMT genotype and cannabis use in early stages of psychosis and its effects on the age of onset in a representative group of first-episode psychosis patients. Age of onset, DUP (Duration of Untreated Psychosis) and cannabis use (regular user versus sporadic or non-user) were assessed in 169 Caucasian patients with a first-episode schizophrenia spectrum disorder. COMT polymorphism was typed using PCR of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with DUP and age of onset as dependent variables, cannabis and the COMT genotype as fixed factors, and gender as a covariate. The MANCOVA was significant for age of onset and DUP. Cannabis users had a significant earlier age of onset. Age of onset was later in the Met homozygote group (non-significant). The cannabis-COMT interaction showed a significant effect on both DUP and age of onset. Post hoc analyses showed that differences between genotypes were only present in the non-users' group. Based on these results, the use of cannabis could exert a modulator effect on the genotype, suppressing the delay effect for the age of onset in the case of the Met allele patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 377 | Psychiatry Res 2010 Dec 180: 153-5 |
| PMID | 20483173 |
| Title | Association study of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism with auditory P300 in Chinese Han patients with schizophrenia. |
| Abstract | Several studies have reported associations between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and P300 event-related potentials in schizophrenic patients. But there has been no research to study the association between the P300 component and the Val158Met polymorphism in Chinese Han schizophrenia patients. Therefore, the present article was aimed at investigating the relationship of the Val158Met polymorphism with P300 in Chinese schizophrenic patients. The Val158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 287 schizophrenia patients and 84 healthy control subjects. P300 recordings were obtained in a subsample. A significant difference was not observed between the patients and control subjects in the genotype distributions and allele frequencies. P300 amplitude in schizophrenia patients was significantly lower than that of controls. The P300 latency in schizophrenia patients was also significantly longer than that of controls. The P300 latency of Met homozygotes was significantly shorter than that of Val/Met and of Val/Val carriers at Cz and Pz. The latency of Val/Met carriers was significantly shorter than that of Val/Val carriers at Pz. The results did not suggest an association between the polymorphism in the COMT gene and susceptibility to schizophrenia in the Chinese Han population. However, the COMT Val158Met polymorphism might be a susceptibility variant for P300 abnormality in Chinese Han schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 378 | J Psychiatr Res 2010 Oct 44: 971-8 |
| PMID | 20398908 |
| Title | Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients. |
| Abstract | Copy number variations (CNV) have become an important source of human genome variability noteworthy to consider when studying genetic susceptibility to complex diseases. As recent studies have found evidences for the potential involvement of CNVs in psychiatric disorders, we have studied the dosage effect of structural genome variants as a possible susceptibility factor for different psychiatric disorders in a candidate gene approach. After selection of 68 psychiatric disorders' candidate genes overlapping with CNVs, MLPA assays were designed to determine changes in copy number of these genes. The studied sample consisted of 724 patients with psychiatric disorders (accounting for anxiety disorders, mood disorders, eating disorders and schizophrenia) and 341 control individuals. CNVs were detected in 30 out of the 68 genes screened, indicating that a considerable proportion of neuronal pathways genes contain CNVs. When testing the overall burden of rare structural genomic variants in the different psychiatric disorders compared to control individuals, there was no statistically significant difference in the total amount of gains and losses. However, 14 out of the 30 changes were only found in psychiatric disorder patients but not in control individuals. These genes include GRM7, previously associated to major depression disorder and bipolar disorder, SLC6A13, in anxiety disorders, and S100B, SSTR5 and COMT in schizophrenia. Although we have not been able to found a clear association between the studied CNVs and psychiatric disorders, the rare variants found only within the patients could account for a step further towards understanding the pathophysiology of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 379 | Neuropsychopharmacology 2010 Jul 35: 1708-17 |
| PMID | 20357758 |
| Title | Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT. |
| Abstract | Gamma-aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 (p=0.005) and rs769390 (p=0.004)) showed effects on GABA levels as did COMT val158met (p=0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p=0.001 and 0.003, respectively) and a trend toward a significant interaction (p=0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N=6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 380 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jun 153B: 948-54 |
| PMID | 20127886 |
| Title | Sexually dimorphic interaction between the DRD1 and COMT genes in schizophrenia. |
| Abstract | Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 381 | Neuroimage 2010 Nov 53: 1043-50 |
| PMID | 20123031 |
| Title | The effects of gender and catechol O-methyltransferase (COMT) Val108/158Met polymorphism on emotion regulation in velo-cardio-facial syndrome (22q11.2 deletion syndrome): An fMRI study. |
| Abstract | Velo-cardio-facial syndrome (VCFS) is caused by a micro-deletion of over 40 genes at the q11.2 locus of chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. COMT, one of the genes located in the deleted region, has been considered as a major candidate gene for genetic susceptibility in psychiatric diseases. Its functional polymorphism Val108/158Met has been shown to affect prefrontal function and working memory and has been associated with emotional dysregulation. We utilized a functional magnetic resonance imaging (fMRI) event-related paradigm to asses COMT genotype and gender-moderated effects on the neural activation that are elicited by viewing emotionally salient images charged with pleasant, unpleasant, and neutral content. Since estrogen down-regulates COMT activity resulting in lower COMT activity in women than men, we hypothesized an allele-by-gender interaction effect on neural activation. Participants included 43 VCFS individuals (Val/male=9, Val/female=17, Met/male=9, Met/female=8). We observed a gender effect on processing positive emotions, in that girls activated the cingulate gyrus more than boys did. We further observed a significant gender-by-allele interaction effect on neural function specific to the frontal lobe during the processing of pleasant stimuli, and specific to limbic regions during the processing of unpleasant stimuli. Our results suggest that in VCFS, the effect of the COMT Val108/158Met polymorphism is moderated by gender during the processing of emotional stimuli and could contribute to the understanding of the way in which this COMT polymorphism affects vulnerability to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 382 | J Affect Disord 2010 Sep 125: 341-4 |
| PMID | 20122740 |
| Title | Association between catechol-O-methyltransferase Val(108/158)Met polymorphism and psychotic features of bipolar disorder. |
| Abstract | Catechol-O-methyltransferase (COMT) inactivates catecholamines, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity and the interaction between cortical and subcortical dopaminergic neurotransmission. Studies in healthy participants and in patients affected by schizophrenia suggested that rs4680 can influence the propensity to develop psychotic symptoms, with the Met low-activity allele exerting a protective role. Previous studies in bipolar patients reported non-significant trends in the same direction. We genotyped rs4680 in a sample of 467 patients affected by bipolar disorder type I with or without a previous illness episode with psychotic features (DSM-IV criteria: delusions or hallucinations). We observed a significant association between homozygosis for the rs4680 COMT low-activity variant and a reduced risk of experiencing illness episodes with psychotic features during the course of the illness. The Met/Met genotype was more common among patients without psychotic features, and while in the non-psychotic group the Val/Val genotype had a distribution similar to Met/Met, in the group of patients who experienced episodes with psychotic symptoms the proportion of Val/Val homozygotes was the double of Met/Met. We suggest that rs4680 could be an inheritable aspect of the mechanisms of dopamine regulation that could influence the individual susceptibility of patients with bipolar disorder to develop psychotic symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 383 | Schizophr. Res. 2010 May 118: 98-105 |
| PMID | 20083391 |
| Title | A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case-control and family-based sample of German ancestry. |
| Abstract | Dysbindin (DTNBP1) is a widely studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity. Six hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parent-offspring trios were genotyped for 38 Dysbindin SNPs. We also studied two phenotypically-defined subsamples: 147 patients with a positive family history of SCZ (FH-SCZ+) and SCZ patients characterized for cognitive performance with Trail-Making Tests A and B (TMT-A: n=219; TMT-B: n=247). Given previous evidence of gene-gene interactions in SCZ involving the COMT gene, we also assessed epistatic interactions between Dysbindin markers and 14 SNPs in COMT. No association was detected between Dysbindin markers and SCZ, or in the FH-SCZ+ subgroup. Only one marker (rs1047631, previously reported to be part of a risk haplotype), showed a nominally significant association with performance on TMT-A and TMT-B; these findings did not remain significant after correction for multiple comparisons. Similarly, no pair-wise epistatic interactions between Dysbindin and COMT markers remained significant after correction for 504 pair-wise comparisons. Our results, based on one of the largest samples of European Caucasians and using narrowly-defined criteria for SCZ, do not support the etiological involvement of Dysbindin markers in SCZ. Larger samples may be needed in order to unravel Dysbindin's possible role in the genetic basis of proposed intermediate phenotypes of SCZ or to detect epistatic interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 384 | Neuroimage 2010 Nov 53: 978-84 |
| PMID | 20060911 |
| Title | COMT genotype and its role on hippocampal-prefrontal regions in declarative memory. |
| Abstract | Memory dysfunction is a prominent feature in schizophrenia. Impairments of declarative memory have been consistently linked to alterations especially within hippocampal-prefrontal regions. Due to the high heritability of schizophrenia, susceptibility genes and their modulatory impact on the neural correlates on memory are of major relevance. In the present study the influence of the COMT val(158)met status on the neural correlates of declarative memory was investigated in healthy subjects. From an initial behavioural sample of 522 healthy individuals (Sheldrick et al., 2008), 84 subjects underwent fMRI scanning while performing a memory encoding and a retrieval task. The COMT val(158)met status was determined for the whole sample and correlated with cortical activation within the group of n=84 individuals. There were no effects of COMT status on behavioural performance. For declarative memory processing the number of met alleles predicted circumscribed bilateral insula and anterior hippocampus activations during memory encoding as well as less deactivations within the bilateral posterior parahippocampal gyri during memory retrieval. Although declarative memory performance was unaffected, the neural correlates within hippocampal-prefrontal regions demonstrate a link between COMT val(158)met carrier status and brain areas associated with declarative memory processing. The study contributes to a better understanding of the role that susceptibility genes might play in the aetiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 385 | Neuroimage 2010 Nov 53: 992-1000 |
| PMID | 20026221 |
| Title | The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults. |
| Abstract | Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 386 | Acta Neurobiol Exp (Wars) 2010 -1 70: 86-94 |
| PMID | 20407490 |
| Title | Influence of dopaminergic and serotoninergic genes on working memory in healthy subjects. |
| Abstract | Working memory is an ability to keep information in short-term memory and manipulate them 'on line'. Working memory is also involved in complex frontal executive functions. The role of dopaminergic system in modulating working memory processes in prefrontal cortex is well established. Also the role of serotoninergic receptors is postulated. The purpose of this study was to assess the association between the polymorphisms of dopaminergic (DRD1, DRD3, DRD4, COMT) and serotoninergic (SERT--serotonin transporter, 5HT2A, 5HT2C) genes' polymorphisms and performance on WCST in 200 volunteers from the Polish population. We found the association between DRD1, DRD4, COMT and SERT genes polymorphisms and the performance on WCST. The results obtained in the study indicate that dopaminergic and serotoninergic genes may play a role in modulating the executive function and working memory processes in healthy subjects. The pattern of this influence may be different in males and females. Moreover, the relationship between the efficacy of prefrontal cognitive function and genes polymorphisms may differ between healthy subjects and schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 387 | Biol. Psychiatry 2010 Feb 67: 287-90 |
| PMID | 19892319 |
| Title | Catechol-o-methyltransferase valine(158)methionine genotype and resting regional cerebral blood flow in medication-free patients with schizophrenia. |
| Abstract | A valine(158)methionine (val(158)met) polymorphism in catechol-O-methyltransferase (COMT) modulates cortical dopaminergic catabolism and has been associated with schizophrenia. Consistent with schizophrenia itself, during cognitive tasks, the risk (val) allele predicts less efficient prefrontal cortex (PFC) physiology and worse performance, while during aversive stimuli viewing, this allele predicts less limbic activation. Task-independent effects of this polymorphism in schizophrenia have not yet been characterized. Twenty-five medication-free patients (28 +/- 6 years; 19 male patients) and 47 healthy individuals (29 +/- 8 years; 33 male individuals) were genotyped for the COMT val(158)met polymorphism and underwent two 60-second radiolabeled water ([(15)O]H(2)O) regional cerebral blood flow (rCBF) positron emission tomography scans (10 mCi/scan) during rest. Data were analyzed with a random-effects general linear model using COMT genotype as a covariate. In patients, but not healthy individuals, val (risk) allele load predicted less regional cerebral blood flow in the right dorsolateral PFC, right superior temporal gyrus, and left precuneus, but greater rCBF in the amygdala and parahippocampal gyrus. In schizophrenia, brain structures important for executive and affective processing show activity that is differentially predicted by COMT allelic variation in an opposing manner even at rest, providing evidence for the salience of prefrontal dopaminergic tone in task-independent, basal-level neural activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 388 | Schizophr Bull 2010 Mar 36: 341-6 |
| PMID | 18635674 |
| Title | Sensorimotor gating of schizophrenia patients depends on Catechol O-methyltransferase Val158Met polymorphism. |
| Abstract | It has been recently shown that Catechol O-methyltransferase (COMT) Val(158)Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val(158)Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val(158)Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val(158)Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val(158)Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 389 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 79-85 |
| PMID | 19367610 |
| Title | Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients. |
| Abstract | The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol-O-methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy-Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2-SNP haplotype analysis (rs4818-Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 390 | Mol. Psychiatry 2010 Feb 15: 216-25 |
| PMID | 18574484 |
| Title | The complex global pattern of genetic variation and linkage disequilibrium at catechol-O-methyltransferase. |
| Abstract | Genetic variation at the catechol-O-methyltransferase (COMT) gene has been significantly associated with risk for various neuropsychiatric conditions such as schizophrenia, panic disorder, bipolar disorders, anorexia nervosa and others. It has also been associated with nicotine dependence, sensitivity to pain and cognitive dysfunctions especially in schizophrenia. The non-synonymous single nucleotide polymorphism (SNP) in exon 4--Val108/158Met--is the most studied SNP at COMT and is the basis for most associations. It is not, however, the only variation in the gene; several haplotypes exist across the gene. Some studies indicate that the haplotypic combinations of alleles at the Val108/158Met SNP with those in the promoter region and in the 3'-untranslated region are responsible for the associations with disorders and not the non-synonymous SNP by itself. We have now studied DNA samples from 45 populations for 63 SNPs in a region of 172 kb across the region of 22q11.2 encompassing the COMT gene. We focused on 28 SNPs spanning the COMT-coding region and immediately flanking DNA, and found that the haplotypes are from diverse evolutionary lineages that could harbor as yet undetected variants with functional consequences. Future association studies should be based on SNPs that define the common haplotypes in the population(s) being studied. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 391 | Schizophr Bull 2010 Jan 36: 157-64 |
| PMID | 18562342 |
| Title | Catechol-O-methyltransferase Val 158 Met polymorphism and antisaccade eye movements in schizophrenia. |
| Abstract | The catechol-O-methyltransferase (COMT) enzyme catabolizes dopamine. The val(158)met single nucleotide polymorphism (rs4680) in the COMT gene has received considerable attention as a candidate gene for schizophrenia as well as for frontally mediated cognitive functions. Antisaccade performance is a good measure of frontal lobe integrity. Deficits on the task are considered a trait marker for schizophrenia. The aim of this study was to investigate the association of COMT val(158)met polymorphism with antisaccade eye movements in schizophrenia patients and healthy controls. schizophrenia patients (N = 105) and healthy controls (N = 95) underwent infrared oculographic assessment of antisaccades. Subjects were genotyped for COMT val(158)met and divided into 3 groups according to genotype (val/val, val/met, and met/met). Patients displayed significantly more reflexive errors, longer and more variable latency, and lower amplitude gain than controls (all P < 0.02). A greater number of val(158) alleles was associated with shorter (P = 0.045) and less variable (P = 0.028) antisaccade latency and, nonsignificantly, with lower reflexive error rate (P = 0.056). None of these variables showed a group-by-genotype interaction (P > 0.1). There were no significant associations of genotype with measures of amplitude gain or spatial error (P > 0.2). The results suggest that COMT val(158) carrier status is associated with better performance on the antisaccade task. Possible explanations of this finding are discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 392 | Behav. Genet. 2010 May 40: 415-23 |
| PMID | 20033274 |
| Title | Catechol-o-methyltransferase genotype and childhood trauma may interact to impact schizotypal personality traits. |
| Abstract | We attempt to identify gene by childhood abuse interactions which predispose to the development of schizotypal traits in a familial bipolar disorder (BD) sample. Self-report measures of schizotypal personality traits (schizotypal Personality Scale) and childhood maltreatment (Childhood Trauma Questionnaire) were administered to 222 participants from 44 families with BD. Variants of catechol-o-methyltransferase (COMT) and four other dopamine pathway-related genes: DRD4, DRD2,MAOA, and SLC6A3, were typed. BD type I (BD I) subjects scored significantly higher than their unaffected relatives on the schizotypal Personality Scale. The val allele of the Val158 Met polymorphism of the COMT gene was associated with increased schizotypal personality trait scores in individuals exposed to higher levels of self-reported childhood trauma (p < 0.05). There was no direct effect of the val158met polymorphism on schizotypal personality traits. Further, no passive correlation between COMT genotype and childhood trauma was found. We raise the possibility that genetically-driven variation in COMT may interact with childhood trauma to contribute to the risk of developing schizotypal personality traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 393 | Psychiatry Res 2010 Dec 180: 153-5 |
| PMID | 20483173 |
| Title | Association study of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism with auditory P300 in Chinese Han patients with schizophrenia. |
| Abstract | Several studies have reported associations between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and P300 event-related potentials in schizophrenic patients. But there has been no research to study the association between the P300 component and the Val158Met polymorphism in Chinese Han schizophrenia patients. Therefore, the present article was aimed at investigating the relationship of the Val158Met polymorphism with P300 in Chinese schizophrenic patients. The Val158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 287 schizophrenia patients and 84 healthy control subjects. P300 recordings were obtained in a subsample. A significant difference was not observed between the patients and control subjects in the genotype distributions and allele frequencies. P300 amplitude in schizophrenia patients was significantly lower than that of controls. The P300 latency in schizophrenia patients was also significantly longer than that of controls. The P300 latency of Met homozygotes was significantly shorter than that of Val/Met and of Val/Val carriers at Cz and Pz. The latency of Val/Met carriers was significantly shorter than that of Val/Val carriers at Pz. The results did not suggest an association between the polymorphism in the COMT gene and susceptibility to schizophrenia in the Chinese Han population. However, the COMT Val158Met polymorphism might be a susceptibility variant for P300 abnormality in Chinese Han schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 394 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jun 153B: 948-54 |
| PMID | 20127886 |
| Title | Sexually dimorphic interaction between the DRD1 and COMT genes in schizophrenia. |
| Abstract | Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 395 | Neuroimage 2010 Nov 53: 992-1000 |
| PMID | 20026221 |
| Title | The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults. |
| Abstract | Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 396 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 79-85 |
| PMID | 19367610 |
| Title | Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients. |
| Abstract | The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol-O-methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy-Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2-SNP haplotype analysis (rs4818-Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 397 | J Neurodev Disord 2010 Jun 2: 77-92 |
| PMID | 22127856 |
| Title | White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents. |
| Abstract | Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume in the same individual. We used DT-MRI and structural MRI (sMRI) with voxel based morphometry (VBM) to compare, respectively, the fractional anisotropy (FA) and WM volume of 11 children and adolescents with 22q11DS and 12 controls. Also, within 22q11DS we related differences in WM to severity of schizotypy, and polymorphism of the catechol-O-methyltransferase (COMT) gene. People with 22q11DS had significantly lower FA in inter-hemispheric and brainstem and frontal, parietal and temporal lobe regions after covarying for IQ. Significant WM volumetric increases were found in the internal capsule, anterior brainstem and frontal and occipital lobes. There was a significant negative correlation between increased schizotypy scores and reduced WM FA in the right posterior limb of internal capsule and the right body and left splenium of corpus callosum. Finally, the Val allele of COMT was associated with a significant reduction in both FA and volume of WM in the frontal lobes, cingulum and corpus callosum. Young people with 22q11DS have significant differences in both WM microstructure and volume. Also, there is preliminary evidence that within 22q11DS, some regional differences in FA are associated with allelic variation in COMT and may perhaps also be associated with schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 398 | N Am J Med Sci 2011 Apr 3: 176-8 |
| PMID | 22540087 |
| Title | No association between Val158Met of the COMT gene and susceptibility to schizophrenia in the Syrian population. |
| Abstract | The Val158Met single nucleotide polymorphism of the COMT gene has been implicated in the aetiology of schizophrenia, although results from different populations have been conflicting. The aim of the present study was to investigate possible association between schizophrenia and Val158Met in a novel Arab population from Syria. 71 unrelated schizophrenic subjects (45 men) and 102 unrelated healthy controls (62 men) were recruited to take part in this case- control study. The Val158Met of the COMT gene was genotyped for patients and controls, using a new optimized PCR-RFLP method. the results demonstrated that there is no statistically significant difference between the two groups. This study does not support that Val158Met has an influence on susceptibility for schizophrenia in this population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 399 | Psychol Med 2011 Feb 41: 263-76 |
| PMID | 20102668 |
| Title | Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis? |
| Abstract | Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 400 | Encephale 2011 Dec 37 Suppl 2: S127-32 |
| PMID | 22212842 |
| Title | [Schizophrenia, genetics and cognition]. |
| Abstract | schizophrenia is a complex and heritable disorder. Nevertheless, molecular genetics of schizophrenia remains inconclusive. By developing the concept of endophenotype for the disorder, it is easier to define an association between a phenotype and genetic variants or physiopathological processes. Cognitive disorders could be useful endophenotypes for schizophrenia. For example, the val(158)/met COMT polymorphism has been associated with executive function or working memory. Therefore, several cognitive dysfunctions were proposed as endophenotypes and were investigated in the context of different genetic polymorphisms. Genome-wide association studies and epistatic studies demonstrated the complexity of the mechanisms underlying cognitive disturbance. However, meta-analysis remains inconclusive. Altogether, the study of endophenotypes is an attractive approach to solve the complex mechanisms causing schizophrenia vulnerability. Nevertheless, several limitations exist and include the lack of reproducibility, the discordant results between healthy subjects and patients, the exclusion of the many rare variants. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 401 | Genet. Mol. Res. 2011 -1 10: 1850-5 |
| PMID | 21948748 |
| Title | No evidence for association between DRD3 and COMT with schizophrenia in a Malay population. |
| Abstract | Molecular components of the dopamine D3 receptor (DRD3) may play an important role in the pathophysiology of schizophrenia. Previous studies have demonstrated an association between DRD3 Ser9Gly and cathechol-o-methyltransferase (COMT, SNP = rs165656) polymorphisms and schizophrenia but the results were inconclusive. We investigated this apparent association between Ser9Gly (A/G) polymorphism and an intronic SNP (dbSNP or rs165656) in 261 Malay patients diagnosed with schizophrenia and 216 controls, using PCR-RFLP. The genotype distribution of the polymorphism DRD3 Ser9Gly was in Hardy-Weinberg equilibrium (HWE) for patients (P = 0.1251) and out of HWE for controls (P = 0.0137). However, both healthy controls and schizophrenia patients were out of HWE for the polymorphism COMT rs165656. Based on allele and genotype frequencies in both groups, we found no significant association of DRD3 Ser9Gly polymorphisms and COMT (rs165656) with schizophrenia in Malays. Further studies should examine the association between other dopamine-related genes and the behavioral phenotypes of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 402 | Pharmacogenomics 2011 Apr 12: 559-66 |
| PMID | 21521027 |
| Title | Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. |
| Abstract | It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available antipsychotics fail to improve cognitive and negative symptoms originating from this deficit. Evidence from basic science has revealed the importance of prefrontal dopamine signaling for optimal prefrontal function. This article describes succinctly the progress made so far, taking into account the mechanisms involved in catechol-O-methyltransferase (COMT)-induced modulation of prefrontal dopamine signaling, the impact of COMT on cognitive function and the role of COMT gene polymorphisms. The potential role of the COMT inhibitor tolcapone to improve cognitive function in health and disease is also presented here. It will soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotype-specific, targeted treatments of cognitive and negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 403 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2011 Apr 28: 208-11 |
| PMID | 21462137 |
| Title | [An association study of COMT gene polymorphisms with schizophrenia]. |
| Abstract | To investigate the association between 8 polymorphisms in the catechol-O-methyl transferase gene (COMT) and schizophrenia in Yuedong-Chaoshan region of China. Eight single nucleotide polymorphism (SNPs), namely rs4680, rs4818, rs165599, rs737865, rs2075507, rs6267, rs6269 and rs4633, in the COMT gene were genotyped in 279 schizophrenia patients and 100 healthy controls. There was no significant difference between any single SNP and schizophrenia. However, association might exist between haplotypes (G)-G-A-A [(rs4680)-rs165599-rs2075507-rs6269] and A-A-C-(G) [rs2075507-rs6269-rs4633-(rs6267)] and schizophrenia. In the population of Yuedong region of China, the eight SNPs (rs4680, rs4818, rs165599, rs737865, rs2075507, rs6267, rs6269 and rs4633) in the COMT gene are unlikely to play a major role in the susceptibility to schizophrenia. There might be protective haplotypes in the COMT gene against schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 404 | Neurosci. Lett. 2011 May 495: 17-21 |
| PMID | 21402125 |
| Title | Effect of COMT genotype on aggressive behaviour in a community cohort of schizophrenic patients. |
| Abstract | Although the etiology of aggression is multifactorial, many studies have associated the Val158Met polymorphism of the COMT with aggression in schizophrenia. This study tests the hypothesis that Met/Met patients display more episodes of aggression and violent behaviour than Val/Val patients in a 6 year follow-up cohort of subjects with schizophrenia in contact with the South-Verona Community-based Mental Health Service. Out of the 141 subjects with an ICD-10 SCAN-confirmed diagnosis of schizophrenia, 115 completed both baseline and follow-up assessments (81.6% of the baseline cohort). Of these, 80 subjects (70%) were genotyped and rated for aggression using the Overt Aggression Scale. Met/Met homozygous patients had higher aggressive behaviour compared to Val/Val homozygous subjects. Antipsychotic dosage, alcohol and drug abuse were taken into account as confounders. The Met/Met genotype of COMT may have an effect on aggressive behaviour in schizophrenia because norepinephrine is less effectively inactivated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 405 | Expert Opin Drug Metab Toxicol 2011 Jan 7: 9-37 |
| PMID | 21162693 |
| Title | Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. |
| Abstract | Antipsychotic drug is the mainstay of treatment for schizophrenia, and there are large inter-individual differences in clinical response and side effects. Pharmacogenetics provides a valuable tool to fulfill the promise of personalized medicine by tailoring treatment based on one's genetic markers. This article reviews the pharmacogenetic literature from early 1990s to 2010, focusing on two aspects of drug action: pharmacokinetics and pharmacodynamics. Genetic variants in the neurotransmitter receptors including dopamine and 5-HT and metabolic pathways of drugs including CYP2D6 and COMT were discussed in association with clinical drug response and side effects. Readers are expected to learn the up-to-date evidence in pharmacogenetic research and to gain familiarity to the issues and challenges facing the field. Pharmacogenetic research of antipsychotic drugs is both promising and challenging. There is consistent evidence that some genetic variants can affect clinical response and side effects. However, more studies that are designed specifically to test pharmacogenetic hypotheses are clearly needed to advance the field. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 406 | Hum Psychopharmacol 2011 Aug 26: 386-91 |
| PMID | 21823169 |
| Title | Genetic interactions in the adrenergic system genes: analysis of antipsychotic-induced weight gain. |
| Abstract | Atypical antipsychotics (AP) have high affinity for many neurotransmitter receptors. Among these receptors, APs are antagonist at ?-adrenergic and ?-adrenergic receptors, and this pharmacological property has been postulated to be involved in the mechanism of action of these drugs with respect to both clinical response and adverse effects. We tested the hypotheses that AP-induced weight gain is associated with genetic variation in adrenergic receptors and pathway enzymes. We analyzed nine genetic polymorphisms across seven adrenergic genes (ADRA1A, ADRA2A, ADRA2C, ADRB3, DBH, MAOA and COMT). One hundred thirty-nine patients with schizophrenia were prospectively assessed for AP-induced weight gain. The HelixTree software (Golden Helix, Bozeman, MT, USA) was employed to detect differences in genotypic distribution between weight gainer and non-weight gainer groups. Furthermore, for the dopamine ?-hydroxylase haplotype, we were able to obtain both the molecular and the statistical phases, analyzing the phenotype considering both phases. Weight gain was not associated with any adrenergic gene. Our results suggest that genetic polymorphisms in the adrenergic system may not play a major role in AP-induced weight gain; however, adrenergic 2A receptor gene that produced previously the most consistent associations with this phenotype showed a significant interaction with the monoamine oxidase A in weight gainers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 407 | Neuropsychopharmacol Hung 2011 Dec 13: 205-10 |
| PMID | 22184188 |
| Title | Genetic predisposition to schizophrenia: what did we learn and what does the future hold? |
| Abstract | schizophrenia is a complex, devastating brain disorder with clear genetic and environmental contributions to the emergence of the disease. In the last several decades of research hundreds of millions of dollars were spent of the elusive search for schizophrenia susceptibility genes, but the results have been meager. Researchers have identified a number of genetic variants that predispose the brain to developing the disease, yet alone they can explain only a very small number of the schizophrenia occurrence. Vulnerability in DISC1, NRG1, DTNBP1, RGS4, KCNH2, COMT, AKT1 and other putative schizophrenia genes, together with copy number variants, leave unexplained the vast majority of diseased cases. Furthermore, most of the uncovered disease-associated genetic variants have been inconsistently replicated across multiple cohorts and do not lead to altered protein structure. In summary, we argue that large-scale genetic studies will not provide us with the answers we seek: we have to accept that there are no schizophrenia-predisposing genes with large effect sizes, and due to the diversity of findings, genetics-based novel therapies of schizophrenia are not realistic. The new treatments will have to come from functional studies of intracellular pathways and understanding the confluence of environmental influences and genetic predisposition, and their combined effects on developmental mechanisms and intracellular cascades. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 408 | J Neural Transm (Vienna) 2011 Nov 118: 1621-39 |
| PMID | 21688113 |
| Title | Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder. |
| Abstract | Studies examining intermediate phenotypes such as neurocognitive and neuroanatomical measures along with susceptibility genes are important for improving our understanding of the neural basis of schizophrenia (SZ) and bipolar disorder (BD). In this paper, we review extant studies involving neurocognitive-genetic and neuroimaging-genetic perspectives and particularly related to catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin-1 (NRG1) genes in SZ and BD. In terms of neurocognitive-genetic investigations, COMT and BDNF are the two most studied candidate genes especially in patients with SZ. Whereas BDNF Met carriers perform worse on verbal working memory, problem solving and visuo-spatial abilities, COMT Met carriers perform better in working memory, attention, executive functioning with evidence of genotype by diagnosis interactions including high-risk individuals. In terms of genetic-structural MRI studies, patients with SZ are found to have reductions in the frontal, temporal, parietal cortices, and limbic regions, which are associated with BDNF, COMT, and NRGI genes. Genetic-functional MRI studies in psychotic disorders are sparse, especially with regard to BD. These neurocognitive and neuroimaging findings are associated with genes which are implicated in functional pathways related to neuronal signaling, inter-neuronal communication and neuroplasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 409 | Brain Res. 2011 Mar 1377: 21-31 |
| PMID | 21195697 |
| Title | The effects of catechol-O-methyl-transferase polymorphism Val158Met on functional connectivity in healthy young females: a resting EEG study. |
| Abstract | The catechol-O-methyl-transferase (COMT) gene has been linked to a wide spectrum of human phenotypes, including cognition, affective response, pain sensitivity, anxiety and psychosis. This study examined the modulatory effects of COMT Val158Met on neural interactions, indicated by connectivity strengths. Blood samples and resting state eyes-closed EEG signals were collected in 254 healthy young females. The COMT Val158Met polymorphism was decoded into 3 groups: Val/Val, Val/Met and Met/Met. The values of mutual information of 20 frontal-related channel pairs across delta, theta, alpha and beta frequencies were analyzed based on the time-frequency mutual information method. Our one-way ANOVA analyses revealed that the significant connection-frequency pairs were relatively left lateralized (P<0.01) and included F7-T3 and F7-C3 at delta frequency, and F3-F4, F7-T3, F7-C3, F7-P3, F3-C3, F3-F7 and F4-F8 at theta frequency. The F-test at F7-T3 and F7-C3 theta surpassed the statistical threshold of P<0.003 (after Bonferroni correction). For all the above connection-frequency pairs, there was a dose-dependent trend in the connectivity strengths of the alleles as follows: Val/Val>Val/Met>Met/Met. Our analyses complemented previous literature regarding neural modulation by the COMT Val158Met polymorphism. The implication to the pathogenesis in schizophrenia was also discussed. Further studies are needed to clarify whether there is gender difference on this gene-brain interaction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 410 | PLoS ONE 2011 -1 6: e29283 |
| PMID | 22216231 |
| Title | Catechol-O-methyltransferase Val158Met polymorphism associates with individual differences in sleep physiologic responses to chronic sleep loss. |
| Abstract | The COMT Val158Met polymorphism modulates cortical dopaminergic catabolism, and predicts individual differences in prefrontal executive functioning in healthy adults and schizophrenic patients, and associates with EEG differences during sleep loss. We assessed whether the COMT Val158Met polymorphism was a novel marker in healthy adults of differential vulnerability to chronic partial sleep deprivation (PSD), a condition distinct from total sleep loss and one experienced by millions on a daily and persistent basis. 20 Met/Met, 64 Val/Met, and 45 Val/Val subjects participated in a protocol of two baseline 10h time in bed (TIB) nights followed by five consecutive 4 h TIB nights. Met/Met subjects showed differentially steeper declines in non-REM EEG slow-wave energy (SWE)-the putative homeostatic marker of sleep drive-during PSD, despite comparable baseline SWE declines. Val/Val subjects showed differentially smaller increases in slow-wave sleep and smaller reductions in stage 2 sleep during PSD, and had more stage 1 sleep across nights and a shorter baseline REM sleep latency. The genotypes, however, did not differ in performance across various executive function and cognitive tasks and showed comparable increases in subjective and physiological sleepiness in response to chronic sleep loss. Met/Met genotypic and Met allelic frequencies were higher in whites than African Americans. The COMT Val158Met polymorphism may be a genetic biomarker for predicting individual differences in sleep physiology-but not in cognitive and executive functioning-resulting from sleep loss in a healthy, racially-diverse adult population of men and women. Beyond healthy sleepers, our results may also provide insight for predicting sleep loss responses in patients with schizophrenia and other psychiatric disorders, since these groups repeatedly experience chronically-curtailed sleep and demonstrate COMT-related treatment responses and risk factors for symptom exacerbation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 411 | Behav Brain Funct 2011 -1 7: 51 |
| PMID | 22208661 |
| Title | A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study. |
| Abstract | It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated. To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence. The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. Individuals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases. Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 412 | Curr. Mol. Med. 2011 Dec 11: 732-43 |
| PMID | 21999147 |
| Title | Diverse facets of COMT: from a plausible predictive marker to a potential drug target for schizophrenia. |
| Abstract | Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 413 | PLoS ONE 2011 -1 6: e25882 |
| PMID | 21998713 |
| Title | Proline and COMT status affect visual connectivity in children with 22q11.2 deletion syndrome. |
| Abstract | Individuals with the 22q11.2 deletion syndrome (22q11DS) are at increased risk for schizophrenia and Autism Spectrum Disorders (ASDs). Given the prevalence of visual processing deficits in these three disorders, a causal relationship between genes in the deleted region of chromosome 22 and visual processing is likely. Therefore, 22q11DS may represent a unique model to understand the neurobiology of visual processing deficits related with ASD and psychosis. We measured Event-Related Potentials (ERPs) during a texture segregation task in 58 children with 22q11DS and 100 age-matched controls. The C1 component was used to index afferent activity of visual cortex area V1; the texture negativity wave provided a measure for the integrity of recurrent connections in the visual cortical system. COMT genotype and plasma proline levels were assessed in 22q11DS individuals. Children with 22q11DS showed enhanced feedforward activity starting from 70 ms after visual presentation. ERP activity related to visual feedback activity was reduced in the 22q11DS group, which was seen as less texture negativity around 150 ms post presentation. Within the 22q11DS group we further demonstrated an association between high plasma proline levels and aberrant feedback/feedforward ratios, which was moderated by the COMT(158) genotype. These findings confirm the presence of early visual processing deficits in 22q11DS. We discuss these in terms of dysfunctional synaptic plasticity in early visual processing areas, possibly associated with deviant dopaminergic and glutamatergic transmission. As such, our findings may serve as a promising biomarker related to the development of schizophrenia among 22q11DS individuals. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 414 | Schizophr Bull 2011 Sep 37: 913-20 |
| PMID | 21860037 |
| Title | Neurobiology of aggression and violence in schizophrenia. |
| Abstract | There is much evidence that schizophrenia patients have an increased risk for aggression and violent behavior, including homicide. The neurobiological basis and correlates of this risk have not been much studied. While genome-wide association studies are lacking, a number of candidate genes have been investigated. By far, the most intensively studied is the catechol-O-methyltransferase (COMT) gene on chromosome 22. COMT is involved in the metabolism of dopamine, a key neurotransmitter in schizophrenia pathophysiology. Several studies suggest that the Val158Met polymorphism of this gene affects COMT activity. Methionine (Met)/Met homozygote schizophrenia patients show 4- to 5-fold lower COMT activity than valine (Val)/Val homozygotes, and some but not all studies have found an association with aggression and violence. Recently, a new functional single-nucleotide polymorphism in the COMT gene, Ala72Ser, was found to be associated with homicidal behavior in schizophrenia, but this finding warrants further replication. Studies published so far indicate that an association with the monoamine oxidase A, B, or tryptophan hydroxylase 1 genes is unlikely. Data for the brain-derived neurotrophic factor gene are conflicting and limited. Data from the limited number of neuroimaging studies performed to date are interesting. Frontal and temporal lobe abnormalities are found consistently in aggressive schizophrenia patients. Positron emission tomography and single photon-emission computed tomography (SPECT) data indicate deficits also in the orbitofrontal and temporal cortex. Some functional magnetic resonance imaging studies found a negative association of violent behavior with frontal and right-sided inferior parietal activity. Neuroimaging studies may well help further elucidate the interrelationship between neurocognitive functioning, personality traits, and antisocial and violent behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 415 | J Psychiatr Res 2011 Nov 45: 1432-8 |
| PMID | 21820670 |
| Title | DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder. |
| Abstract | The failure in the discovery of etiology of psychiatric diseases, despite extensive genetic studies, has directed the attention of neuroscientists to the contribution of epigenetic modulations, which play important roles in fine-tuning of gene expression in response to environmental factors. Previously, we analyzed 115 human post-mortem brain samples from the frontal lobe and reported DNA hypo methylation of the membrane-bound catechol-O-methyltransferase (MB-COMT) gene promoter, associated with an increased gene expression, as a risk factor for schizophrenia (SCZ) and bipolar disorder (BD). Since most epigenetic modifications are tissue specific and the availability of brain tissue to identify epigenetic aberrations in living subjects is limited, detection of epigenetic abnormalities in other tissues that represent the brain epigenetic marks is one of the critical steps to develop diagnostic and therapeutic biomarkers for mental diseases. Here, hypothesizing that; those factors that lead to the brain MB-COMT promoter DNA hypo-methylation may also cause concurrent epigenetic aberrations in peripheral tissues, we analyzed MB-COMT promoter methylation in DNA derived from the saliva in SCZ, BD and their first-degree relatives (20 cases each) as well as 25 control subjects. Using bisulfite DNA sequencing and quantitative methylation specific PCR (qMSP), we found that similar to the brain, MB-COMT promoter was hypo-methylated (?50%) in DNA derived from the saliva in SCZ and BD compared to the control subjects (p = 0.02 and 0.037, respectively). These studies suggest that DNA methylation analysis of MB-COMT promoter in saliva can potentially be used as an available epigenetic biomarker for disease state in SCZ and BD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 416 | Neuroimage 2011 Aug 57: 1517-23 |
| PMID | 21620981 |
| Title | Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls. |
| Abstract | Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. It remains unclear however if variations in dopamine signaling influence rates of structural cortical maturation in typically developing individuals, and whether such influences are disrupted in patients with schizophrenia and their non-psychotic siblings. We sought to address these issues by relating a functional Val?Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)-a key enzymatic regulator of cortical dopamine levels-to longitudinal structural neuroimaging measures of cortical gray matter thickness. We included a total of 792 magnetic resonance imaging brain scans, acquired between ages 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls. Whereas greater Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, it attenuated cortical thinning in healthy controls. This similarity between COS patients and their siblings was accompanied by differences between the two groups in the timing and spatial distribution of disrupted COMT influences on cortical maturation. Consequently, whereas greater Val "dose" conferred persistent dorsolateral prefrontal cortical deficits amongst affected probands by adulthood, cortical thickness differences associated with varying Val dose in non-psychotic siblings resolved over the age-range studied. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 417 | J Neurodev Disord 2011 Mar 3: 76-85 |
| PMID | 21475729 |
| Title | Atypical development of the executive attention network in children with chromosome 22q11.2 deletion syndrome. |
| Abstract | Impairment in the executive control of attention has been found in youth with chromosome 22q11.2 deletion syndrome (22q11.2DS). However, how this impairment is modified by other factors, particularly age, is unknown. Forty-six typically developing and 53 children with 22q11.2DS were tested with the attention networks task (ANT) in this cross-sectional study. We used logarithmic transform and linear modeling to assess age effects on the executive index of the ANT. Mixed modeling accounted for between subject variability, age, handedness, catecholamine-O-transferase (COMT; codon 158) genotype, and gender on performance for all experimental conditions (cue?×?flanker) and their two-level interactions. Children with 22q11.2DS showed a relative, age-dependent executive index impairment but not orienting or alerting network index impairments. In factorial analysis, age was a major predictor of overall performance. There was a significant effect of the 22q11.2DS on overall performance. Of note, children with 22q11.2DS are specifically vulnerable to incongruent flanker interference, especially at younger ages. We did not find an overall effect of COMT genotype or handedness. Children with 22q11.2DS demonstrated age-related impairment in the executive control of attention. Future investigation will likely reveal that there are different developmental trajectories of executive attentional function likely related to the development of schizophrenia in 22q11.2DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 418 | Neurosci. Lett. 2011 Jun 496: 65-9 |
| PMID | 21458532 |
| Title | No association between the Catechol-O-Methyltransferase (COMT) val158met polymorphism and cognitive improvement following cognitive remediation therapy (CRT) in schizophrenia. |
| Abstract | Cognitive deficits are rate limiters on recovery in schizophrenia that respond poorly to pharmacotherapy. Cognitive remediation therapy (CRT), a novel psychological therapy, has produced promising outcomes for cognition. However, little is known about the biological mechanisms that might underlie individual differences in CRT response. Catechol-O-Methyltransferase (COMT) is associated specifically with prefrontal cognition. The COMT Val158Met polymorphism is known to have a functional effect on the rate of dopamine degradation, which may be related to cognitive treatment response. This study aimed to determine whether COMT genotype influences cognitive improvement following CRT in schizophrenia. Participants with schizophrenia were recruited from three randomised controlled trials of CRT compared to treatment as usual, and one CRT treatment only trial, each providing 40 CRT sessions. Eighty-seven participants (40%) agreed to participate in the genetic study, and provided DNA for COMT genotyping. Cognitive function and psychopathology were assessed at baseline, post-treatment and 3-6-month follow-up. People with the COMT Val/Met genotype performed more poorly on categories achieved at baseline on the Wisconsin Card Sorting Test (WCST) than those homozygous for the Val or Met allele. Cognitive function improved with CRT but there was no association between this cognitive improvement and COMT genotype, either in the CRT group or in the total sample. The COMT val158Met polymorphism does not appear to be a clinically useful biomarker of cognitive improvement following CRT in schizophrenia. A complex set of factors may influence cognitive change, however, such that the COMT genotype might still have a subtle effect on response to CRT or similar interventions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 419 | J. Psychopharmacol. (Oxford) 2011 Jul 25: 888-95 |
| PMID | 21447540 |
| Title | Dopamine metabolism in adults with 22q11 deletion syndrome, with and without schizophrenia--relationship with COMT Val¹??/¹??Met polymorphism, gender and symptomatology. |
| Abstract | 22q11 Deletion syndrome (22q11DS) is a major risk factor for schizophrenia. In addition, both conditions are associated with alterations of the dopaminergic system. The catechol-O-methyltransferase (COMT) gene, located within the deleted region, encodes for the enzyme COMT that is important for degradation of catecholamines, including dopamine (DA). COMT activity is sexually dimorphic and its gene contains a functional polymorphism, Val¹??/¹?? Met; the Met allele is associated with lower enzyme activity. We report the first controlled catecholamine study in 22q11DS-related schizophrenia. Twelve adults with 22q11DS with schizophrenia (SCZ+) and 22 adults with 22q11DS without schizophrenia (SCZ-) were genotyped for the COMT Val¹??/¹?? Met genotype. We assessed dopaminergic markers in urine and plasma. We also correlated these markers with scores on the Positive and Negative Symptom Scale (PANSS). Contrary to our expectations, we found SCZ+ subjects to be more often Val hemizygous and SCZ- subjects more often Met hemizygous. Significant COMT cross gender interactions were found on dopaminergic markers. In SCZ+ subjects there was a negative correlation between prolactin levels and scores on the general psychopathology subscale of the PANSS scores. These findings suggest intriguing, but complex, interactions of the COMT Val¹??/¹?? Met polymorphism, gender and additional factors on DA metabolism, and its relationship with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 420 | Psychiatry Res 2011 Aug 189: 67-71 |
| PMID | 21414668 |
| Title | Association of the functional polymorphism in the catechol-O-methyltransferase gene with schizophrenia in the three ethnic groups of the Malaysian population. |
| Abstract | The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia as its encoded enzyme is involved in the metabolic inactivation of dopamine and noradrenaline. Several molecular genetic studies thus far have demonstrated that the COMT functional polymorphism of Val158Met is susceptible with schizophrenia. Hence, the present study aims to determine this genetic association of this SNP in the three major ethnic groups of the Malaysian population. A total of 317 patients (79 Malays, 154 Chinese and 84 Indians) meeting DSM-IV criteria for schizophrenia and 417 healthy subjects (160 Malays, 164 Chinese and 93 Indians) were recruited. A PCR-RFLP method was used to determine the genotypes and alleles present. We found a significant association of genotypes within the total pooled samples, as well as in the female subgroup, with a higher frequency of heterozygotes in schizophrenia subjects. However, there were no significant differences in allele and genotype frequency between the schizophrenic patients and normal controls in all three ethnic groups. Our current findings suggest that the Val158Met polymorphism has a weak association with schizophrenia in the Malaysian population and does not play a major role in conferring susceptibility to the schizophrenia in any of the three major local ethnicities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 421 | Schizophr. Res. 2011 Apr 127: 22-7 |
| PMID | 21310591 |
| Title | Interaction between COMT haplotypes and cannabis in schizophrenia: a case-only study in two samples from Spain. |
| Abstract | Cannabis use is one of the environmental factors with more solid evidence contributing to schizophrenia risk, especially in genetically susceptible individuals. One of the genes that may interact with cannabis is COMT, although available data are scarce. Here, we present a case-only study of the putative COMT-cannabis interaction in schizophrenia. Two Spanish samples from Santiago de Compostela and Valencia were screened for cannabis use. One hundred and fifty five individuals from a total of 748 patients were identified as cannabis users. Five SNPs in COMT, defining three common functional haplotypes with different enzymatic activities, were genotyped and analyzed for association at the SNP, haplotype and genotype levels. An association was detected between cannabis use and low activity variants (P<0.01) in the joint analysis and results were consistent between the two samples. schizophrenic subjects homozygous for the Met allele at rs4680 doubled the probability of lifetime prevalence of cannabis use in comparison to Val homozygous (Mantel-Haenszel OR=2.07, 95% CI: 1.27-3.26, P=0.0031, in the combined sample). These data are in contrast to those from Caspi et al. (Biol. Psychiatry 57 (2005)1117-1127) who found association between schizophrenia/schizophreniform disorder and homozygosity at the high activity Val variant of rs4680. The results of our study are discussed in the context of previous findings, suggesting the involvement of COMT polymorphisms in the association between cannabis use and schizophrenia as well as the existence of additional factors mediating this association. However, further research is needed to confirm the COMT-cannabis interaction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 422 | Psychol Med 2011 Mar 41: 611-8 |
| PMID | 21272388 |
| Title | Effects of two dopamine-modulating genes (DAT1 9/10 and COMT Val/Met) on n-back working memory performance in healthy volunteers. |
| Abstract | Impairments in working memory are present in many psychiatric illnesses such as attention-deficit hyperactivity disorder (ADHD) and schizophrenia. The dopamine transporter and catechol-O-methyltransferase (COMT) are proteins involved in dopamine clearance and the dopamine system is implicated in the modulation of working memory (WM) processes and neurochemical models of psychiatric diseases. The effects of functional polymorphisms of the dopamine transporter gene (DAT1) and the COMT gene were investigated using a visuospatial and numerical n-back working memory paradigm. Our n-back task was designed to reflect WM alone, and made no demands on higher executive functioning. A total of 291 healthy volunteers (aged 18-45 years) were genotyped and matched for age, sex, and Barratt Impulsivity Scale (BIS) and National Adult Reading Test (NART) scores. To assess individual gene effects on WM, factorial mixed model analysis of variances (ANOVAs) were conducted with the between-subjects factor as genotype and difficulty level (0-, 1-, 2- and 3-back) entered as the within-subjects factor. The analysis revealed that the DAT1 or COMT genotype alone or in combination did not predict performance on the n-back task in our sample of healthy volunteers. Behavioral effects of DAT1 and COMT polymorphisms on WM in healthy volunteers may be non-existent, or too subtle to identify without exceedingly large sample sizes. It is proposed that neuroimaging may provide more powerful means of elucidating the modulatory influences of these polymorphisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 423 | Genes Brain Behav. 2011 Apr 10: 316-24 |
| PMID | 21255265 |
| Title | Association study of catechol-O-methyltransferase gene polymorphisms with schizophrenia and psychopathological symptoms in Han Chinese. |
| Abstract | Although dysfunction of catechol-O-methyltransferase (COMT)-mediated dopamine transmission is implicated in the etiology of schizophrenia, the human COMT gene has not been associated consistently with schizophrenia. The purpose of this study was to investigate whether the COMT gene is associated with the development of schizophrenia and whether the polymorphisms of this gene influence the psychopathological symptoms in patients with schizophrenia. Fourteen polymorphisms of the COMT gene were analyzed in a case-control study of 876 Han Chinese individuals (434 patients and 442 controls). All participants were screened using a Chinese version of the modified Schedule for Affective Disorders and schizophrenia-Lifetime Version (SADS-L) and all patients met the criteria for schizophrenia. Furthermore, pretreatment of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 224 hospitalized schizophrenia patients, who were drug-naÏve or drug-free, to examine the association between clinical symptomatology and COMT polymorphisms. No significant differences in allele or genotype frequencies were observed between schizophrenia patients and controls, for all variants investigated. Haplotype analysis showed that three haplotype blocks of the COMT gene were not associated with the development of schizophrenia. Moreover, these COMT polymorphisms did not influence the PANSS scores of schizophrenia patients. This study suggests that the COMT gene may not contribute to the risk of schizophrenia and to the psychopathological symptoms of schizophrenia among Han Chinese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 424 | Psychiatr. Genet. 2011 Apr 21: 98-105 |
| PMID | 21233783 |
| Title | COMT (Val(158/108)Met) genotype moderates the impact of antipsychotic medication on verbal IQ in twins with schizophrenia. |
| Abstract | In this study, we aimed to assess the moderating effects of the catechol-O-methyl transferase (COMT) (Val(158/108)Met) genotype on antipsychotic medication-induced changes in the cognitive performance of patients with chronic schizophrenia. The sample consisted of 85 monozygotic and 53 dizygotic twin pairs, of varying concordance for schizophrenia, and healthy control twins. Cognitive ability was measured using the Wechsler Adult Intelligence Scale-third edition. We used structural equation modelling to estimate main and interaction effects of the COMT status and antipsychotic medication dose on verbal intelligence quotient (VIQ) and performance intelligence quotient scores. There was no evidence of a main or interaction effect of the COMT status or chlorpromazine equivalent dose on the performance intelligence quotient. There were no main effects of COMT or chlorpromazine equivalent dose on VIQ; however, there was evidence of a statistically significant interaction (P<0.01) between the COMT and chlorpromazine equivalents on VIQ. The VIQ performance of val/val individuals was significantly lower with increasing antipsychotic medication dose, up to 12 intelligence quotient points lower than met carriers treated with medication. In the absence of medication, the three genotypes did not significantly differ, whereas at the highest doses (1500), the val/val homozygotes and Met carriers differed by more than one standard deviation. Our results show that the verbal abilities of val homozygotes of the COMT gene are cognitively impaired by higher doses of antipsychotic medication. This association is reversed in Met carriers. These data are consistent with an earlier study that found evidence of moderating effects of antipsychotic medication on N-back and verbal fluency tasks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 425 | Acta Psychiatr Scand 2011 Jun 123: 485-92 |
| PMID | 21231925 |
| Title | Cannabis use and age at onset of psychosis: further evidence of interaction with COMT Val158Met polymorphism. |
| Abstract | To examine, in a sample of young psychiatric patients, (n = 157, mean age 17.01 years (SD = 3.6)) whether i) age at first cannabis use and age at emergence of psychiatric disorders are related and ii) such a relationship is modulated by the Val158Met polymorphism in the COMT gene. Cannabis use profiles and COMT Val158Met genotypes were obtained from 80 inpatients with schizophrenia-spectrum disorders and 77 inpatients with other non-psychotic disorders. First, age at first cannabis use correlates with age at onset in both schizophrenia-spectrum and other psychiatric disorder groups: those who started using cannabis earlier had an earlier age at onset of psychiatric disorders. Second, the distribution of the Val158Met genotypes was not different either between diagnosis groups or between cannabis users and non-users. Third, an interaction between Val158Met genotypes and cannabis use was observed specifically on age at emergence of psychotic disorders, with Val/Val genotype carriers showing an earlier age at onset than Met carriers. Our results suggest the importance of brain maturation timing in which exposure to cannabis occurs. The COMT Val158Met genotype seems to modulate the association between cannabis and age at onset of psychotic disorders. These results are consistent with previous studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 426 | Biol. Psychiatry 2011 May 69: 1006-8 |
| PMID | 21215384 |
| Title | Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex. |
| Abstract | Accumulating evidence indicates that genetic polymorphisms of D-amino acid oxidase activator (DAOA) (M24; rs1421292; T-allele) and catechol-O-methyltransferase (COMT) (Val¹??Met; rs4680) likely enhance susceptibility to schizophrenia. Previously, clinical association between DAOA M24 (T-allele) and a functionally inefficient 3-marker COMT haplotype (that included COMT Val¹??Met) uncovered epistatic effects on risk for schizophrenia. Therefore, we projected that healthy control subjects with risk genotypes for both DAOA M24 (T/T) and COMT Val¹??Met (Val/Val) would produce prefrontal inefficiency, a critical physiological marker of the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients influenced by both familial and heritable factors. With 3T blood oxygen level dependent functional magnetic resonance imaging data, we analyzed in SPM5 the proposed interaction of DAOA and COMT in 82 healthy volunteers performing an N-back executive working memory paradigm (2-back > 0-back). As predicted, we detected a functional gene x gene interaction between DAOA and COMT in the DLPFC. The neuroimaging findings here of inefficient information processing in the prefrontal cortex seem to echo prior statistical epistasis between risk alleles for DAOA and COMT, albeit within a small sample. These in vivo results suggest that deleterious genotypes for DAOA and COMT might contribute to the pathophysiology of schizophrenia, perhaps through combined glutamatergic and dopaminergic dysregulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 427 | Transl Psychiatry 2011 -1 1: e15 |
| PMID | 22832518 |
| Title | Prefrontal dopamine and the dynamic control of human long-term memory. |
| Abstract | Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long-term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final test-a phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism. The COMT Val(108/158)Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 428 | Psychol Med 2011 Aug 41: 1721-31 |
| PMID | 21144115 |
| Title | Catechol-O-methyltransferase Val(158)Met association with parahippocampal physiology during memory encoding in schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) Val158Met has been associated with activity of the mesial temporal lobe during episodic memory and it may weakly increase risk for schizophrenia. However, how this variant affects parahippocampal and hippocampal physiology when dopamine transmission is perturbed is unclear. The aim of the present study was to compare the effects of the COMT Val158Met genotype on parahippocampal and hippocampal physiology during encoding of recognition memory in patients with schizophrenia and in healthy subjects. Using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), we studied 28 patients with schizophrenia and 33 healthy subjects matched for a series of sociodemographic and genetic variables while they performed a recognition memory task. We found that healthy subjects had greater parahippocampal and hippocampal activity during memory encoding compared to patients with schizophrenia. We also found different activity of the parahippocampal region between healthy subjects and patients with schizophrenia as a function of the COMT genotype, in that the predicted COMT Met allele dose effect had an opposite direction in controls and patients. Our results demonstrate a COMT Val158Met genotype by diagnosis interaction in parahippocampal activity during memory encoding and may suggest that modulation of dopamine signaling interacts with other disease-related processes in determining the phenotype of parahippocampal physiology in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 429 | J Psychiatr Res 2011 Mar 45: 322-31 |
| PMID | 20817203 |
| Title | Developmental changes in multivariate neuroanatomical patterns that predict risk for psychosis in 22q11.2 deletion syndrome. |
| Abstract | The primary objective of the current prospective study was to examine developmental patterns of voxel-by-voxel gray and white matter volumes (GMV, WMV, respectively) that would predict psychosis in adolescents with 22q11.2 deletion syndrome (22q11.2DS), the most common known genetic risk factor for schizophrenia. We performed a longitudinal voxel-based morphometry analysis using structural T1 MRI scans from 19 individuals with 22q11.2DS and 18 typically developing individuals. In 22q11.2DS, univariate analysis showed that greater reduction in left dorsal prefrontal cortical (dPFC) GMV over time predicted greater psychotic symptoms at Time2. This dPFC region also showed significantly reduced volumes in 22q11.2DS compared to typically developing individuals at Time1 and 2, greater reduction over time in 22q11.2DS COMT(Met) compared to COMT(Val), and greater reduction in those with greater decline in verbal IQ over time. Leave-one-out Multivariate pattern analysis results (MVPA) on the other hand, showed that patterns of GM and WM morphometric changes over time in regions including but not limited to the dPFC predicted risk for psychotic symptoms (94.7-100% accuracy) significantly better than using univariate analysis (63.1%). Additional predictive brain regions included medial PFC and dorsal cingulum. This longitudinal prospective study shows novel evidence of morphometric spatial patterns predicting the development of psychotic symptoms in 22q11.2DS, and further elucidates the abnormal maturational processes in 22q11.2DS. The use of neuroimaging using MVPA may hold promise to predict outcome in a variety of neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 430 | J Psychiatr Res 2011 Jan 45: 7-14 |
| PMID | 20488458 |
| Title | Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. |
| Abstract | Catechol-O-methyltransferase (COMT) has been largely studied in relation to schizophrenia susceptibility. Most studies focused on the functional single nucleotide polymorphism (SNP) rs4680 that causes a substitution of Val by Met at codon 158 of the COMT protein. Recent meta-analyses do not support an association between allelic variants at rs4680 and schizophrenia. However, the putative role of overdominance has not been tested in meta-analyses, despite its biological plausibility. In this work, we tested the overdominant model in two Spanish samples (from Valencia and Santiago de Compostela), representing a total of 762 schizophrenic patients and 1042 controls, and performed a meta-analysis of the available studies under this model. A total of 51 studies comprising 13,894 schizophrenic patients and 16,087 controls were included in the meta-analysis, that revealed a small but significant protective effect for heterozygosity at rs4680 (pooled OR=0.947, P=0.023). Post-hoc analysis on southwestern European samples suggested a stronger effect in these populations (pooled OR=0.813, P=0.0009). Thus, the COMT functional polymorphism rs4680 contributes to schizophrenia genetic susceptibility under an overdominant model, indicating that both too high and too low levels of dopamine (DA) signalling may be risk factors. This effect can be modulated by genetic background. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 431 | N Am J Med Sci 2011 Apr 3: 176-8 |
| PMID | 22540087 |
| Title | No association between Val158Met of the COMT gene and susceptibility to schizophrenia in the Syrian population. |
| Abstract | The Val158Met single nucleotide polymorphism of the COMT gene has been implicated in the aetiology of schizophrenia, although results from different populations have been conflicting. The aim of the present study was to investigate possible association between schizophrenia and Val158Met in a novel Arab population from Syria. 71 unrelated schizophrenic subjects (45 men) and 102 unrelated healthy controls (62 men) were recruited to take part in this case- control study. The Val158Met of the COMT gene was genotyped for patients and controls, using a new optimized PCR-RFLP method. the results demonstrated that there is no statistically significant difference between the two groups. This study does not support that Val158Met has an influence on susceptibility for schizophrenia in this population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 432 | Neurosci. Lett. 2011 May 495: 17-21 |
| PMID | 21402125 |
| Title | Effect of COMT genotype on aggressive behaviour in a community cohort of schizophrenic patients. |
| Abstract | Although the etiology of aggression is multifactorial, many studies have associated the Val158Met polymorphism of the COMT with aggression in schizophrenia. This study tests the hypothesis that Met/Met patients display more episodes of aggression and violent behaviour than Val/Val patients in a 6 year follow-up cohort of subjects with schizophrenia in contact with the South-Verona Community-based Mental Health Service. Out of the 141 subjects with an ICD-10 SCAN-confirmed diagnosis of schizophrenia, 115 completed both baseline and follow-up assessments (81.6% of the baseline cohort). Of these, 80 subjects (70%) were genotyped and rated for aggression using the Overt Aggression Scale. Met/Met homozygous patients had higher aggressive behaviour compared to Val/Val homozygous subjects. Antipsychotic dosage, alcohol and drug abuse were taken into account as confounders. The Met/Met genotype of COMT may have an effect on aggressive behaviour in schizophrenia because norepinephrine is less effectively inactivated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 433 | PLoS ONE 2011 -1 6: e29283 |
| PMID | 22216231 |
| Title | Catechol-O-methyltransferase Val158Met polymorphism associates with individual differences in sleep physiologic responses to chronic sleep loss. |
| Abstract | The COMT Val158Met polymorphism modulates cortical dopaminergic catabolism, and predicts individual differences in prefrontal executive functioning in healthy adults and schizophrenic patients, and associates with EEG differences during sleep loss. We assessed whether the COMT Val158Met polymorphism was a novel marker in healthy adults of differential vulnerability to chronic partial sleep deprivation (PSD), a condition distinct from total sleep loss and one experienced by millions on a daily and persistent basis. 20 Met/Met, 64 Val/Met, and 45 Val/Val subjects participated in a protocol of two baseline 10h time in bed (TIB) nights followed by five consecutive 4 h TIB nights. Met/Met subjects showed differentially steeper declines in non-REM EEG slow-wave energy (SWE)-the putative homeostatic marker of sleep drive-during PSD, despite comparable baseline SWE declines. Val/Val subjects showed differentially smaller increases in slow-wave sleep and smaller reductions in stage 2 sleep during PSD, and had more stage 1 sleep across nights and a shorter baseline REM sleep latency. The genotypes, however, did not differ in performance across various executive function and cognitive tasks and showed comparable increases in subjective and physiological sleepiness in response to chronic sleep loss. Met/Met genotypic and Met allelic frequencies were higher in whites than African Americans. The COMT Val158Met polymorphism may be a genetic biomarker for predicting individual differences in sleep physiology-but not in cognitive and executive functioning-resulting from sleep loss in a healthy, racially-diverse adult population of men and women. Beyond healthy sleepers, our results may also provide insight for predicting sleep loss responses in patients with schizophrenia and other psychiatric disorders, since these groups repeatedly experience chronically-curtailed sleep and demonstrate COMT-related treatment responses and risk factors for symptom exacerbation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 434 | Psychiatry Res 2011 Aug 189: 67-71 |
| PMID | 21414668 |
| Title | Association of the functional polymorphism in the catechol-O-methyltransferase gene with schizophrenia in the three ethnic groups of the Malaysian population. |
| Abstract | The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia as its encoded enzyme is involved in the metabolic inactivation of dopamine and noradrenaline. Several molecular genetic studies thus far have demonstrated that the COMT functional polymorphism of Val158Met is susceptible with schizophrenia. Hence, the present study aims to determine this genetic association of this SNP in the three major ethnic groups of the Malaysian population. A total of 317 patients (79 Malays, 154 Chinese and 84 Indians) meeting DSM-IV criteria for schizophrenia and 417 healthy subjects (160 Malays, 164 Chinese and 93 Indians) were recruited. A PCR-RFLP method was used to determine the genotypes and alleles present. We found a significant association of genotypes within the total pooled samples, as well as in the female subgroup, with a higher frequency of heterozygotes in schizophrenia subjects. However, there were no significant differences in allele and genotype frequency between the schizophrenic patients and normal controls in all three ethnic groups. Our current findings suggest that the Val158Met polymorphism has a weak association with schizophrenia in the Malaysian population and does not play a major role in conferring susceptibility to the schizophrenia in any of the three major local ethnicities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 435 | Schizophr. Res. 2011 Apr 127: 22-7 |
| PMID | 21310591 |
| Title | Interaction between COMT haplotypes and cannabis in schizophrenia: a case-only study in two samples from Spain. |
| Abstract | Cannabis use is one of the environmental factors with more solid evidence contributing to schizophrenia risk, especially in genetically susceptible individuals. One of the genes that may interact with cannabis is COMT, although available data are scarce. Here, we present a case-only study of the putative COMT-cannabis interaction in schizophrenia. Two Spanish samples from Santiago de Compostela and Valencia were screened for cannabis use. One hundred and fifty five individuals from a total of 748 patients were identified as cannabis users. Five SNPs in COMT, defining three common functional haplotypes with different enzymatic activities, were genotyped and analyzed for association at the SNP, haplotype and genotype levels. An association was detected between cannabis use and low activity variants (P<0.01) in the joint analysis and results were consistent between the two samples. schizophrenic subjects homozygous for the Met allele at rs4680 doubled the probability of lifetime prevalence of cannabis use in comparison to Val homozygous (Mantel-Haenszel OR=2.07, 95% CI: 1.27-3.26, P=0.0031, in the combined sample). These data are in contrast to those from Caspi et al. (Biol. Psychiatry 57 (2005)1117-1127) who found association between schizophrenia/schizophreniform disorder and homozygosity at the high activity Val variant of rs4680. The results of our study are discussed in the context of previous findings, suggesting the involvement of COMT polymorphisms in the association between cannabis use and schizophrenia as well as the existence of additional factors mediating this association. However, further research is needed to confirm the COMT-cannabis interaction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 436 | Biol. Psychiatry 2011 May 69: 1006-8 |
| PMID | 21215384 |
| Title | Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex. |
| Abstract | Accumulating evidence indicates that genetic polymorphisms of D-amino acid oxidase activator (DAOA) (M24; rs1421292; T-allele) and catechol-O-methyltransferase (COMT) (Val¹??Met; rs4680) likely enhance susceptibility to schizophrenia. Previously, clinical association between DAOA M24 (T-allele) and a functionally inefficient 3-marker COMT haplotype (that included COMT Val¹??Met) uncovered epistatic effects on risk for schizophrenia. Therefore, we projected that healthy control subjects with risk genotypes for both DAOA M24 (T/T) and COMT Val¹??Met (Val/Val) would produce prefrontal inefficiency, a critical physiological marker of the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients influenced by both familial and heritable factors. With 3T blood oxygen level dependent functional magnetic resonance imaging data, we analyzed in SPM5 the proposed interaction of DAOA and COMT in 82 healthy volunteers performing an N-back executive working memory paradigm (2-back > 0-back). As predicted, we detected a functional gene x gene interaction between DAOA and COMT in the DLPFC. The neuroimaging findings here of inefficient information processing in the prefrontal cortex seem to echo prior statistical epistasis between risk alleles for DAOA and COMT, albeit within a small sample. These in vivo results suggest that deleterious genotypes for DAOA and COMT might contribute to the pathophysiology of schizophrenia, perhaps through combined glutamatergic and dopaminergic dysregulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 437 | J Psychiatr Res 2011 Jan 45: 7-14 |
| PMID | 20488458 |
| Title | Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. |
| Abstract | Catechol-O-methyltransferase (COMT) has been largely studied in relation to schizophrenia susceptibility. Most studies focused on the functional single nucleotide polymorphism (SNP) rs4680 that causes a substitution of Val by Met at codon 158 of the COMT protein. Recent meta-analyses do not support an association between allelic variants at rs4680 and schizophrenia. However, the putative role of overdominance has not been tested in meta-analyses, despite its biological plausibility. In this work, we tested the overdominant model in two Spanish samples (from Valencia and Santiago de Compostela), representing a total of 762 schizophrenic patients and 1042 controls, and performed a meta-analysis of the available studies under this model. A total of 51 studies comprising 13,894 schizophrenic patients and 16,087 controls were included in the meta-analysis, that revealed a small but significant protective effect for heterozygosity at rs4680 (pooled OR=0.947, P=0.023). Post-hoc analysis on southwestern European samples suggested a stronger effect in these populations (pooled OR=0.813, P=0.0009). Thus, the COMT functional polymorphism rs4680 contributes to schizophrenia genetic susceptibility under an overdominant model, indicating that both too high and too low levels of dopamine (DA) signalling may be risk factors. This effect can be modulated by genetic background. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 438 | Curr. Pharm. Des. 2012 -1 18: 5024-35 |
| PMID | 22716151 |
| Title | Gene-environment interactions underlying the effect of cannabis in first episode psychosis. |
| Abstract | Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 439 | Gene 2012 Sep 506: 135-40 |
| PMID | 22771913 |
| Title | Role of the apolipoprotein E and catechol-O-methyltransferase genes in prospective and retrospective memory traits. |
| Abstract | Human memory is a complex neurocognitive process. By combining psychological and molecular genetics expertise, we examined the APOE ?4 allele, a known risk factor for Alzheimer's disease, and the COMT Val 158 polymorphism, previously implicated in schizophrenia, for association with lowered memory functioning in healthy adults. To assess memory type we used a range of memory tests of both retrospective and prospective memory. Genotypes were determined using RFLP analysis and compared with mean memory scores using univariate ANOVAs. Despite a modest sample size (n=197), our study found a significant effect of the APOE ?4 polymorphism in prospective memory. Supporting our hypothesis, a significant difference was demonstrated between genotype groups for means of the Comprehensive Assessment of Prospective Memory total score (p=0.036; ?4 alleles=1.99; all other alleles=1.86). In addition, we demonstrate a significant interactive effect between the APOE ?4 and COMT polymorphisms in semantic memory. This is the first study to investigate both APOE and COMT genotypes in relation to memory in non-pathological adults and provides important information regarding the effect of genetic determinants on human memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 440 | Integr Biol (Camb) 2012 Sep 4: 1096-101 |
| PMID | 22777684 |
| Title | The severity of mental disorders is linked to interaction among candidate genes. |
| Abstract | There is a considerable overlap in the manifestation of symptoms in three mental disorders namely unipolar disorder, bipolar disorder and schizophrenia. A gene coexpression network was developed based on a mutual information approach including four candidate genes (NRG1, DISC1, BDNF and COMT) along with other coexpressing genes in unipolar disorder, bipolar disorder and schizophrenia. There is a significant difference in the degree distribution of nodes between normal and bipolar disorder network and bipolar disorder network and schizophrenia network. Moreover, there is a differential direct connectivity among candidate genes in various mental disorders and between normal and mental disorders. All candidate genes are directly connected to each other in schizophrenia except one pair (NRG1-BDNF) indicating a strong role of inter-gene interactions in the manifestation of severe symptoms in this disease. DISC1 and NRG1 are key hub genes in the unipolar disorder network and the bipolar disorder network but have lost the role of hub genes in schizophrenia network, despite their significant association with schizophrenia. This study indicates that the three psychiatric diseases may not have discrete classes but three phenotypic manifestations of the same continuous disease based on severity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 441 | Arq Neuropsiquiatr 2012 Dec 70: 913-6 |
| PMID | 23295417 |
| Title | Association study between the rs165599 catechol-O-methyltransferase genetic polymorphism and schizophrenia in a Brazilian sample. |
| Abstract | schizophrenia is a severe psychiatric disorder with frequent recurrent psychotic relapses and progressive functional impairment. It results from a poorly understood gene-environment interaction. The gene encoding catechol-O-methyltransferase (COMT) is a likely candidate for schizophrenia. Its rs165599 (A/G) polymorphism has been shown to be associated with alteration of COMT gene expression. Therefore, the present study aimed to investigate a possible association between schizophrenia and this polymorphism. The distribution of the alleles and genotypes of this polymorphism was investigated in a Brazilian sample of 245 patients and 834 controls. The genotypic frequencies were in Hardy-Weinberg equilibrium and no statistically significant differences were found between cases and controls when analyzed according to gender or schizophrenia subtypes. There was also no difference in homozygosis between cases and controls. Thus, in the sample studied, there was no evidence of any association between schizophrenia and rs165599 (A/G) polymorphism in the non-coding region 3' of the COMT gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 442 | Curr Top Med Chem 2012 -1 12: 2303-13 |
| PMID | 23279171 |
| Title | Neuroimaging correlates of 22q11.2 deletion syndrome: implications for schizophrenia research. |
| Abstract | 22q11.2 Deletion syndrome (22q11DS) is the most common known recurrent copy-number variant disorder. It is also the most common known genetic risk factor for schizophrenia. The greater homogeneity of subjects with schizophrenia in 22q11DS compared with schizophrenia in the wider non-deleted population may help to identify much needed information on neuroanatomical substrates, and neurochemical and neurofunctional mechanisms that may modulate the risk for schizophrenia. Identification of the underlying pathophysiology creates opportunities for developing genotype-specific, biology-based and targeted treatments to prevent, delay or minimize the severity of schizophrenia in both 22q11DS and the wider non-deleted population. This article reviews neuroimaging studies that focused on brain structure and function in this high-risk population, with particular attention to schizophrenia research. We also discuss the evidence on the role of candidate genes within the 22q11.2 region, with particular reference to catechol-O-methyl transferase (COMT) and proline dehydrogenase (PRODH). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 443 | Fa Yi Xue Za Zhi 2012 Aug 28: 299-304 |
| PMID | 23033671 |
| Title | [Association and its forensic significance between COMT gene and schizophrenia]. |
| Abstract | Catechol-O-methyltransferase (COMT) gene encodes catechol-O-methyltransferase, the variant of this gene may affect the expression and metabolic activity of COMT. As the result of the changes of the effective concentration of the catecholamine neurotransmitter in the central nervous system, central nervous system dysfunctions associated with schizophrenia. This review summarizes genetic polymorphism and diversity of COMT gene. It also elaborates the relation between SNP and haplotype of COMT gene and three aspects, which including schizophrenia, attacking and violent tendency, and the frontal cognitive function of the schizophreniac. The correlativity study between genetic variation of the COMT gene and schizophrenia in patients with attacking and violent tendency may be helpful for the assessment of forensic psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 444 | Genet Test Mol Biomarkers 2012 Sep 16: 1138-41 |
| PMID | 22963606 |
| Title | No association of catechol-O-methyltransferase polymorphisms with schizophrenia in the Han Chinese population. |
| Abstract | Genetics play a major role in the etiology of schizophrenia (SZ). Catechol-O-methyltransferase (COMT) is one of the promising candidate genes for SZ. A nonsynonymous single-nucleotide polymorphism (SNP), rs4680, causing a Valine (Val) to Methionine (Met) substitution, has been widely studied in relation to psychiatric phenotypes, including SZ, but with conflicting results. We conducted a two-stage study to examine the association of COMT polymorphisms with SZ in the Han Chinese population. Association analysis of nine SNPs in 768 patients and 1348 controls failed to detect any positive markers or haplotypes. Then, we tested rs4680 in a validation sample of 963 patients and 992 controls, and no significant association was observed, but the cases significantly deviated from Hardy-Weinberg equilibrium (p=5.7e-4). There was no association of rs4680 with SZ in the combined sample (n=4071, p=0.110, odds ratio=1.08). Our results do not support the association of COMT with SZ in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 445 | PLoS ONE 2012 -1 7: e43423 |
| PMID | 22905266 |
| Title | A meta-analysis of the Val158Met COMT polymorphism and violent behavior in schizophrenia. |
| Abstract | We conducted a meta-analysis of studies examining the association between the Val158Met COMT polymorphism and violence against others in schizophrenia. A systematic search current to November 1, 2011 was conducted using MEDLINE, EMBASE, CINAHL, PsycINFO, ProQuest, and the National Criminal Justice Reference Service and identified 15 studies comprising 2,370 individuals with schizophrenia for inclusion. Bivariate analyses of study sensitivities and specificities were conducted. This methodology allowed for the calculation of pooled diagnostic odds ratios (DOR). Evidence of a significant association between the presence of a Met allele and violence was found such that men's violence risk increased by approximately 50% for those with at least one Met allele compared with homozygous Val individuals (DOR = 1.45; 95% CI = 1.05-2.00; z = 2.37, p = 0.02). No significant association between the presence of a Met allele and violence was found for women or when outcome was restricted to homicide. We conclude that male schizophrenia patients who carry the low activity Met allele in the COMT gene are at a modestly elevated risk of violence. This finding has potential implications for the pharmacogenetics of violent behavior in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 446 | Bipolar Disord 2012 Aug 14: 554-64 |
| PMID | 22713126 |
| Title | COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. |
| Abstract | The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol-O-methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. Seventy-two symptomatic, medication-free subjects with bipolar I disorder (BD-I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state-dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 447 | Clin. Biochem. 2012 Jul 45: 787-92 |
| PMID | 22560999 |
| Title | Impact of catechol-o-methyltransferase polymorphisms on risperidone treatment for schizophrenia and its potential clinical significance. |
| Abstract | The main aim was to study the effects of COMT polymorphisms on response of risperidone treatment for schizophrenia and investigate the correlation between memory function of schizophrenia patients and COMT polymorphisms. Subjects were 83 schizophrenic patients who were antipsychotic drug free at the initiation of this study. Peripheral blood samples were obtained to identify COMT polymorphisms by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Clinical Global Impressions (CGI), Positive and Negative Syndrome Scale (PANSS) and Wechsler Memory Scale (WMS) test were used to assess the effect of risperidone treatment. The Val/Met carriers showed a significant increase in change of P300 during treatment (P=0.032). Association of Val/Met carriers performed better than other genotypes (P=0.028). The mean plasma concentration of prolactin of Val/Val carriers was significantly lower (P=0.017). The COMT polymorphisms may be a potential biomarker for clinical risperidone treatment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 448 | CNS Neurol Disord Drug Targets 2012 May 11: 292-8 |
| PMID | 22483299 |
| Title | Current understanding of the interplay between catechol-O-methyltransferase genetic variants, sleep, brain development and cognitive performance in schizophrenia. |
| Abstract | Abnormal sleep is an endophenotype of schizophrenia. Here we provide an overview of the genetic mechanisms that link specific sleep physiological processes to schizophrenia-related cognitive defects. In particular, we will review the possible relationships between catechol-O-methyltransferase (COMT), sleep regulation and schizophrenia development. Recent studies validate the hypothesis that COMT mutations may trigger disturbances during adolescence that affect sleep and cortical development. Anomalies in cortical development during this critical developmental phase may increase the susceptibility for schizophrenia. In conclusion, in view of therapeutic efficacy, we can envisage indications for future investigations into the role of COMT for sleep regulation, cognitive performance and sleep-related cognitive deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 449 | CNS Neurol Disord Drug Targets 2012 May 11: 282-91 |
| PMID | 22483298 |
| Title | Catechol-O-methyl transferase as a drug target for schizophrenia. |
| Abstract | Current antipsychotic drugs lack material efficacy against the negative symptoms and cognitive deficits of schizophrenia. There is considerable uncertainty regarding the optimal pharmacotherapeutic strategy for treating these and other aspects of psychotic illness. The present review summarises clinical, mutant, and psychopharmacological data related to catechol-O-methyltransferase (COMT), an enzyme involved in the catabolism of catecholamine neurotransmitters, with a view to establishing the antipsychotic potential of compounds targeting the action of this enzyme. The review examines clinical and preclinical genetic data linking COMT gene variation with risk for schizophrenia or specific symptoms or disease endophenotypes. We then summarise data concerning the behavioural effects of COMT inhibitors. These genetic and pharmacological data relating to COMT as a therapeutic target have implications for the development of individualised treatments for treatment-resistant symptoms of schizophrenia, including cognitive dysfunction and, potentially, negative symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 450 | Mol. Psychiatry 2012 Oct 17: 1007-16 |
| PMID | 21788944 |
| Title | Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. |
| Abstract | AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 451 | Scientifica (Cairo) 2012 -1 2012: 560514 |
| PMID | 24278715 |
| Title | The Association between COMT, BDNF, and NRG1 and Premorbid Social Functioning in Patients with Psychosis, Their Relatives, and Controls. |
| Abstract | We investigated the influences of putative candidate genes for psychosis on premorbid social adjustment and on premorbid schizoid-schizotypal traits. A family-based sample was used including 177 patients with schizophrenia or bipolar I disorder with a history of psychotic symptoms, 86 of their unaffected relatives, and 116 unrelated healthy controls. Association analyses on the combined sample were conducted using the Statistical Analysis for Genetic Epidemiology software (SAGE) and adjusting for age, sex, clinical group, and the family-based nature of the data. The COMT Val(158)Met and BDNF Val(66)Met polymorphisms showed no evidence of association with either phenotype. The SNP rs221533 of the NRG1 gene was significantly associated with premorbid adjustment in adolescence with TT homozygous subjects having a poorer performance than C allele carriers. In the context of neurodevelopmental disorders such as schizophrenia and other psychoses, this finding is plausible; however, it is preliminary and requires replication in an independent sample. In a broader sense, the use of intermediate quantitative phenotypes such as the ones presented in this study may be of help to understand the mechanism of action of genetic risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 452 | Acta Crystallogr. D Biol. Crystallogr. 2012 Mar 68: 253-60 |
| PMID | 22349227 |
| Title | Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors. |
| Abstract | The biological activity of catechol neurotransmitters such as dopamine in the synapse is modulated by transporters and enzymes. Catechol-O-methyltransferase (COMT; EC 2.1.1.6) inactivates neurotransmitters by catalyzing the transfer of a methyl group from S-adenosylmethionine to catechols in the presence of Mg²?. This pathway also inactivates L-DOPA, the standard therapeutic for Parkinson's disease. Depletion of catechol neurotransmitters in the prefrontal cortex has been linked to schizophrenia. The inhibition of COMT therefore promises improvements in the treatment of these diseases. The concept of bisubstrate inhibitors for COMT has been described previously. Here, ribose-modified bisubstrate inhibitors were studied. Three high-resolution crystal structures of COMT in complex with novel ribose-modified bisubstrate inhibitors confirmed the predicted binding mode but displayed subtle alterations at the ribose-binding site. The high affinity of the inhibitors can be convincingly rationalized from the structures, which document the possibility of removing and/or replacing the ribose 3'-hydroxyl group and provide a framework for further inhibitor design. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 453 | ISRN Psychiatry 2012 -1 2012: 651613 |
| PMID | 23762769 |
| Title | Frequency Distribution of COMT Polymorphisms in Greek Patients with Schizophrenia and Controls: A Study of SNPs rs737865, rs4680, and rs165599. |
| Abstract | schizophrenia, a severe psychiatric condition, is characterized by disturbances of cognition, emotion, and social functioning. The disease affects almost 1% of world population. Recent studies evaluating the role of catechol-O-methyltransferase enzyme (COMT) polymorphisms in the pathogenesis of schizophrenia have resulted in ambiguous findings. The current study examined the association of schizophrenia with three COMT polymorphisms, namely, rs737865, rs4680, and rs165599 in a Greek population. There was no significant association between schizophrenia and any of the three SNPs examined. However, haplotype analysis showed that cases have higher frequency of the T-A-A haplotype, and participants with that haplotype were at increased risk for developing schizophrenia (OR = 1.52; CL?:?1.12-2.08; P = 0.008). Furthermore, patients with schizophrenia displayed an excess of TC/AA/AA and the TT/AA/GA genotypes. Similarly a protective effect of TT/GG/GG and TT/GA/GG was suggested by our results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 454 | Psychiatr. Genet. 2012 Apr 22: 92-5 |
| PMID | 21934644 |
| Title | Influence of genetic variability at the COMT gene on TMT-B performance in psychotic patients and their healthy siblings. |
| Abstract | The Val158Met catechol-O-methyl transferase functional polymorphism has been repeatedly associated to differences in performing the Wisconsin Card Sorting Test in both, patients with schizophrenia and healthy individuals. However, this association has not been consistently replicated for the Trail Making Test part-B (TMT-B). In a sample of 89 patients suffering from a functional psychotic disorder and their healthy siblings we aim (i) to explore if there is any difference completing the TMT-B between both groups and among the different psychotic categories, and (ii) to investigate the association between the catechol-O-methyl transferase genotype and the TMT-B performance. Psychotic patients executed the TMT-B worse than the siblings group (P?0.006). The patients (P=0.001) and the siblings (P=0.006) with the Val/Val genotype used more time to execute the test than those who carried the Met allele. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 455 | Psychiatry Res 2012 Jan 195: 83-4 |
| PMID | 21872942 |
| Title | COMT haplotype analyses in Malaysians with schizophrenia. |
| Abstract | The present study included a total 261 patients with schizophrenia and 261 healthy controls to replicate the genetic association between the cathechol-o-methyltransferase gene and schizophrenia using a haplotype block-based gene-tagging. The G-G-G haplotype was found to show a highly significant association with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 456 | Eur. Psychiatry 2012 Jul 27: 372-6 |
| PMID | 20934310 |
| Title | HapMap tag-SNP analysis confirms a role for COMT in schizophrenia risk and reveals a novel association. |
| Abstract | Catechol-O-methyl transferase (COMT) encodes an enzyme involved in the metabolism of dopamine and maps to a commonly deleted region that increases schizophrenia risk. A non-synonymous polymorphism (rs4680) in COMT has been previously found to be associated with schizophrenia and results in altered activity levels of COMT. Using a haplotype block-based gene-tagging approach we conducted an association study of seven COMT single nucleotide polymorphisms (SNPs) in 160 patients with a DSM-IV diagnosis of schizophrenia and 250 controls in an Australian population. Two polymorphisms including rs4680 and rs165774 were found to be significantly associated with schizophrenia. The rs4680 results in a Val/Met substitution but the strongest association was shown by the novel SNP, rs165774, which may still be functional even though it is located in intron five. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. This association was slightly improved when males were analysed separately possibly indicating a degree of sexual dimorphism. Our results confirm that COMT is a good candidate for schizophrenia risk, by replicating the association with rs4680 and identifying a novel SNP association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 457 | Mol. Psychiatry 2012 Sep 17: 887-905 |
| PMID | 22584867 |
| Title | Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. |
| Abstract | We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 458 | Brain 2012 May 135: 1436-45 |
| PMID | 22525159 |
| Title | Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment. |
| Abstract | Working memory is a limited capacity system that integrates and manipulates information across brief periods of time, engaging a network of prefrontal, parietal and subcortical brain regions. Genetic control of these heritable brain processes have been suggested by functional genetic variations influencing dopamine signalling, which affect prefrontal activity during complex working memory tasks. However, less is known about genetic control over component working memory cortical-subcortical networks in humans, and the pharmacogenetic implications of dopamine-related genes on cognition in patients receiving anti-dopaminergic drugs. Here, we examined predictions from basic models of dopaminergic signalling in cortical and cortical-subcortical circuitries implicated in dissociable working memory maintenance and manipulation processes. We also examined pharmacogenetic effects on cognition in the context of anti-dopaminergic drug therapy. Using dynamic causal models of functional magnetic resonance imaging in normal subjects (n?=?46), we identified differentiated effects of functional polymorphisms in COMT, DRD2 and AKT1 genes on prefrontal-parietal and prefrontal-striatal circuits engaged during maintenance and manipulation, respectively. Cortical synaptic dopamine monitored by the COMT Val158Met polymorphism influenced prefrontal control of both parietal processing in working memory maintenance and striatal processing in working memory manipulation. DRD2 and AKT1 polymorphisms implicated in DRD2 signalling influenced only the prefrontal-striatal network associated with manipulation. In the context of anti-psychotic drugs, the DRD2 and AKT1 polymorphisms altered dose-response effects of anti-psychotic drugs on cognition in schizophrenia (n?=?111). Thus, we suggest that genetic modulation of DRD2-AKT1-related prefrontal-subcortical circuits could at least in part influence cognitive dysfunction in psychosis and its treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 459 | BMC Neurosci 2012 -1 13: 95 |
| PMID | 22867132 |
| Title | Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra. |
| Abstract | Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17?-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5?-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5?-reductase mRNA levels. We find ER? and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT) increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ER? mRNA down-regulation and ER? mRNA up-regulation by testosterone was found. 5? reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting conversion of T to DHT and increasing AR mRNA. Further, testosterone may increase local dopamine synthesis and metabolism, thereby changing dopamine regulation within the substantia nigra. We show that testosterone action through both AR and ERs modulates synthesis of sex steroid receptor by altering AR and ER mRNA levels in normal adolescent male substantia nigra. Increased sex steroids in the brain at adolescence may alter substantia nigra dopamine pathways, increasing vulnerability for the development of psychopathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 460 | PLoS ONE 2012 -1 7: e36561 |
| PMID | 22615781 |
| Title | Candidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study. |
| Abstract | Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 10 candidate genes (PPP1R1B, BDNF, DRD3, DRD2, HTR2A, HTR2C, COMT, MnSOD, CYP1A2, and RGS2). Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 31 SNPs, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. VARIOUS SNPS REACHED NOMINAL SIGNIFICANCE: TD and orofacial dyskinesia with rs6265 and rs988748, limb truncal dyskinesia with rs6314, rest tremor with rs6275, rigidity with rs6265 and rs4680, bradykinesia with rs4795390, akathisia with rs4680, tardive dystonia with rs1799732, rs4880 and rs1152746. After controlling for multiple testing, no significant results remained. The findings suggest that selected SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 461 | J. Nerv. Ment. Dis. 2012 Nov 200: 941-5 |
| PMID | 23124177 |
| Title | Psychosocial functioning and cognitive deficits are not associated with membrane-bound catechol-O-methyltransferase deoxyribonucleic acid methylation in siblings of patients with schizophrenia. |
| Abstract | In this study, we investigated whether the siblings of patients with schizophrenia have deficits in cognition and psychosocial functioning and whether the psychosocial functioning and cognitive deficits correlate with the methylation status of the membrane-bound catechol-O-methyltransferase (MB-COMT) gene in peripheral leukocytes. Cognitive abilities were evaluated using the attention/vigilance Continuous Performance Test, delayed/immediate recall scores, the Wisconsin Card Sorting Test, and the Semantic Verbal Fluency Test. Psychosocial functioning was evaluated using the Scale for the Assessment of Negative Symptoms, the Global Assessment of Functioning scale, and the Social Adjustment Scale. A bisulfate-based sequencing was adopted to analyze the methylation status of the MB-COMT promoter in peripheral leukocytes. Significant impairments in attention/vigilance and verbal memory and significant decreases in immediate and delayed recall scores were observed in the siblings of patients with schizophrenia compared with the healthy subjects. In addition, significant deficits in global social functioning and in social interaction were found in the siblings. The tested region of the MB-COMT promoter was generally unmethylated in peripheral leukocytes, without significant correlation with behavioral deficits in the siblings.Our study demonstrated that the siblings have significant deficits in cognition and psychosocial functioning, which may not be associated with MB-COMT methylation in peripheral leukocytes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 462 | J. Psychopharmacol. (Oxford) 2012 Dec 26: 1548-60 |
| PMID | 22952320 |
| Title | Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val(158) Met polymorphism in adults with 22q11 deletion syndrome. |
| Abstract | 22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22, which includes the gene coding for catechol-O-methyl-transferase (COMT). High dopamine (DA) levels due to COMT haplo-insufficiency may be associated with the increased risk of developing schizophrenia in adults with 22q11DS. Reduced prepulse inhibition (PPI) of the acoustic startle response has been associated with schizophrenia and with disrupted DAergic transmission in the prefrontal cortex (PFC). COMT Val(158)Met polymorphism has been shown to influence PPI. We report the first study in adults with 22q11DS to examine PPI of the acoustic startle response and its modulation by COMT Val(158)Met polymorphism. Startle reactivity (SR) and PPI of the acoustic startle response were measured in 23 adults with 22q11DS and 21 healthy controls. 22q11DS subjects were genotyped for the functional COMT Val(158)Met polymorphism. 22q11DS Met hemizygotes showed reduced SR and PPI compared with 22q11DS Val hemizygotes. The effect of COMT Val(158)Met polymorphism on PPI was no longer significant when controlling for baseline SR. Met hemizygosity in 22q11DS is associated with reduced SR and influences PPI indirectly. Decreased PFC functioning following excessive PFC DA levels may be one of the mechanisms by which the Met genotype in 22q11DS disrupts SR. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 463 | Psychiatr. Genet. 2012 Dec 22: 298-9 |
| PMID | 22935916 |
| Title | Association between a COMT polymorphism and clinical response to risperidone treatment: a pharmacogenetic study. |
| Abstract | A total of 130 Chinese schizophrenic patients (45 male, 85 female) were enrolled in the study. Clinical efficacy was determined using Brief Psychiatric Rating Scale (BPRS) scores. We genotyped 10 single-nucleotide polymorphisms (SNPs) of the catechol-O-methyl transferase gene (COMT) in our patients and re-examined them for association with changes in BPRS scores after 8 weeks of risperidone monotherapy. COMT is one of the genes that confer susceptibility to schizophrenia, both because of its role in neurotransmitter metabolism and because of its location in the high-risk schizophrenia-related region 22q11. Recent studies also found that COMT functional polymorphisms influenced individual response to antipsychotic medication. Our aim in this study was to explore the influence of COMT polymorphisms on pharmacological response to risperidone in the Chinese population. Statistical analysis revealed a significant association between an upstream COMT SNP, rs9606186, and scores reduction of BPRS in all patients and in the male subgroup but not in the female subgroup (allele analysis: P=0.055 for all, P=0.012 for male patients; genotype analysis: P=0.046 for all, P=0.020 for male patients, uncorrected, odds ratio=3.95). The COMT gene polymorphism, SNP rs9606186, is associated with risperidone therapy efficiency in the Chinese population. This association exhibited a sexually dimorphic difference, which may shed light on the genetics of COMT and its enzymatic sex-dependent mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 464 | Transl Psychiatry 2012 -1 2: e146 |
| PMID | 22872161 |
| Title | Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome. |
| Abstract | The 22q11.2 microdeletion is one of the highest genetic risk factors for schizophrenia. It is not well understood which interactions of deleted genes in 22q11.2 regions are responsible for the pathogenesis of schizophrenia, but catechol-O-methytransferase (COMT) is among the candidates. Df1/+ mice are 22q11.2 deletion syndrome (22q11DS) model mice with a hemizygous deletion of 18 genes in the 22q11-related region. Df1/+ mice showed enhanced response to the dopamine D1 agonist, SKF38393, and the N-methyl-D-aspartate antagonist, MK801, which can be normalized by a GABA(A) receptor agonist, bretazenil, or a GABA(A) ?2/?3 receptor agonist, SL651498. Here, we demonstrated the curing effects of virus-mediated reintroduction of COMT to the prefrontal cortex (PFC) in Df1/+ mice. In contrast, both COMT overexpression and COMT inhibition caused an abnormal responsiveness to Bretazenil, a GABA(A) receptor agonist in control mice. COMT overexpression increased MK801-induced interneuronal activation and GABA release in the PFC. The expression levels of GABA-related genes such as Gabrb2 (GABA(A)receptor ?2), Gad2 (glutamic acid decarboxylase 65 (Gad65)) and Reln (Reelin) correlate with a COMT expression level in PFC. Our data suggest that COMT-mediated regulation of GABAergic system might be involved in the behavioral pathogenesis of Df1/+ mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 465 | ACS Chem Neurosci 2012 Feb 3: 129-40 |
| PMID | 22860182 |
| Title | Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates. |
| Abstract | Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 466 | Pharmacol Rep 2012 -1 64: 528-35 |
| PMID | 22814006 |
| Title | Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. |
| Abstract | Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 467 | Schizophr. Res. 2012 Sep 140: 192-7 |
| PMID | 22784685 |
| Title | The COMT Met158 allele and violence in schizophrenia: a meta-analysis. |
| Abstract | The Met158 allele of catechol-O-methyl transferase (COMT) gene is associated with increased levels of catecholamines in the prefrontal cortex and may increase the likelihood of aggressiveness. We conducted a meta-analysis to test the hypothesis that the Met158 allele of the COMT gene is associated with aggressive and violent behavior in schizophrenia. MEDLINE search (12/31/11) yielded 14 studies examining the association of the COMT gene polymorphism (rs4680) and aggression in schizophrenia (total n=2219). Three separate analyses were conducted using a random effects model for Met allele carriers vs. Val/Val homozygotes, Met/Met homozygotes vs. Val allele carriers, and Met allele vs. Val allele, respectively. Primary outcome was frequency of patients with aggressive behavior and odds ratio (OR) was the effect size measure. The frequency of violent patients in the sample ranged from 20% to 75%. The pooled effect sizes for the Met homozygotes vs. Val allele carriers, Met allele carriers vs. Val homozygotes and the Met allele vs. Val allele comparisons were 1.74, 1.65 and 1.35, ps<.05, respectively, suggesting that the Met 158 allele of the COMT gene is associated with higher risk for violence in schizophrenia. Results remained significant after examining heterogeneity among samples and potential publication biases. The Met158 allele of the COMT gene confers a significantly increased risk for aggressive and violent behavior in schizophrenia. These data may provide basis for developing informative strategies for reducing violence in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 468 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Oct 39: 163-9 |
| PMID | 22705295 |
| Title | Association of MB-COMT polymorphisms with schizophrenia-susceptibility and symptom severity in an African cohort. |
| Abstract | The catechol-O-methyltransferase (COMT) gene is an attractive schizophrenia candidate gene, encoding a catabolic dopamine enzyme. The enzyme exists as two distinct isoforms, with the membrane bound enzyme (i.e. MB-COMT) being predominantly expressed in the brain. Since African populations remain underrepresented in genetic/genomic research, we performed an association study to determine whether MB-COMT genetic variants are associated with schizophrenia-susceptibility and symptom severity in the South African Xhosa population. Fourteen candidate polymorphisms were selected by means of a literature search and in silico analyses and were subsequently genotyped in a cohort of 238 Xhosa schizophrenia patients and 240 healthy Xhosa controls. Genetic association was tested with schizophrenia-susceptibility as well as symptom severity within the patient group. Polymorphisms of interest were also analysed using functional assays. Two SNPs, rs2020917 (OR=0.54, 95% CI 0.37-0.79; P=0.0011) and rs737865 (OR=0.52, 95% CI 0.36-0.74; P=0.0002), in the P2 promoter region were significantly associated with schizophrenia as well as an increase (increase=11.2%, 95% CI 3.7%-19.2%; P=0.0031) in reporter gene expression. The minor alleles of these SNPs were underrepresented in the schizophrenia cohort, indicating a possible protective effect. The P2 region also formed part of a haplotype found to be associated with the severity of the negative symptoms of the disorder. The data generated by this study indicate that genetic variation of MB-COMT could be associated with schizophrenia and negative symptom severity in the Xhosa population and may therefore be one of the genomic loci contributing towards the disorder in the South African community. Future large-scale studies in other African schizophrenia populations are required to further elucidate the significance of these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 469 | Psychopharmacology (Berl.) 2012 Dec 224: 349-62 |
| PMID | 22700037 |
| Title | Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats. |
| Abstract | Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague-Dawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia. After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH). Startle and PPI were assessed in SD and LE rats administered D-amphetamine (0 vs. 4.5 mg/kg, sc). Two weeks later, brain tissue was processed for COMT, nrg1, grid2, and csnk1e expression; blood COMT expression was also tested. Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE > SD expression in most genes and regions, and female > male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120 ms correlated significantly with NAC nrg1 expression, while amphetamine sensitivity for 30 ms PPI and startle magnitude correlated significantly with VH nrg1 and blood COMT expression. Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 470 | CNS Neurol Disord Drug Targets 2012 May 11: 273-81 |
| PMID | 22483289 |
| Title | COMT implication in cognitive and psychiatric symptoms in chromosome 22q11 microdeletion syndrome: a selective review. |
| Abstract | 22q11.2 deletion syndrome (22q11DS) is a genetic syndrome associated with a microdeletion of the chromosome 22 band q11.2 with an estimated prevalence between 1:2,500 and 1:4,000. Studies of school-age children have shown that individuals with 22q11DS have high rates of psychiatric morbidity. In particular, by late adolescence, about 30% of patients with 22q11DS develop psychotic symptoms. One of the genes located in the microdeletion region of 22q11DS is the Catechol-O-Methyl transferase (COMT) which codes for an enzyme critically involved in the catabolic clearance of dopamine. COMT is critically involved in cognitive related disturbances, and it has often been suggested as a sensitive factor in the development of psychiatric disorders. Several studies have been conducted on the impact of COMT functional polymorphism in 22q11DS and its related cognitive/psychiatric correlates. In this review, we summarize mainly current knowledge on the correlation between schizophrenia/cognitive related symptoms and COMT genetic variations in 22q11DS. A selective literature review on this topic was undertaken. COMT might play an important role in modulating cognitive functions in 22q11DS but a clear relationship between COMT polimorphism and schizophrenia in 22q11DS need further investigation. Despite controversial results, 22q11DS represent a powerful model for studying the role of COMT and other genetic variations in schizophrenia. This is due to high risk in 22qDS patients of developing this disorder and their relative genetic homogeneity. Further research is needed to evaluate all of the polymorphic markers in the COMT gene and its nearby regulatory elements for association with schizophrenia. Identification of specific COMT-dependent molecular, cellular and circuit deficits will provide targets for the development of more efficient treatments for the cognitive and psychiatric symptoms in 22q11DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 471 | PLoS ONE 2012 -1 7: e33473 |
| PMID | 22457764 |
| Title | Functional gene-expression analysis shows involvement of schizophrenia-relevant pathways in patients with 22q11 deletion syndrome. |
| Abstract | 22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's) of 8 22q11DS patients and 8 age- and gender-matched controls, to (1) investigate the expression levels of 22q11 genes and (2) to investigate whether 22q11 genes participate in functional genetic networks relevant to schizophrenia. Functional relationships between genes differentially expressed in patients (as identified by Locally Adaptive Statistical procedure (LAP) or satisfying p<0.05 and fold-change >1.5) were investigated with the Ingenuity Pathways Analysis (IPA). 14 samples (7 patients, 7 controls) passed quality controls. LAP identified 29 deregulated genes. Pathway analysis showed 262 transcripts differentially expressed between patients and controls. Functional pathways most disturbed were cell death, cell morphology, cellular assembly and organization, and cell-to-cell signaling. In addition, 10 canonical pathways were identified, among which the signal pathways for Natural Killer-cells, neurotrophin/Trk, neuregulin, axonal guidance, and Huntington's disease. Our findings support the use of 22q11DS as a research model for schizophrenia. We identified decreased expression of several genes (among which COMT, Ufd1L, PCQAP, and GNB1L) previously linked to schizophrenia as well as involvement of signaling pathways relevant to schizophrenia, of which Neurotrophin/Trk and neuregulin signaling seems to be especially notable. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 472 | Eur Arch Psychiatry Clin Neurosci 2012 Dec 262: 667-76 |
| PMID | 22454241 |
| Title | Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning. |
| Abstract | Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-O-methyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit-specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 473 | Neuropsychopharmacology 2012 Jun 37: 1773-83 |
| PMID | 22434221 |
| Title | Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on indices of dopaminergic, endocannabinoid and GABAergic pathways. |
| Abstract | Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol-O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent cannabis exposure to increase risk for schizophrenia. The impact of such an interaction on central neurotransmitter pathways implicated in schizophrenia is unknown. Male mice with knockout of the COMT gene were treated chronically with delta-9-tetrahydrocannabinol (THC) during adolescence (postnatal day 32-52). We measured the size and density of GABAergic cells and the protein expression of cannabinoid receptor 1 (CB1R) in the prefrontal cortex (PFC) and hippocampus (HPC) in knockout mice relative to heterozygous mutants and wild-type controls. Size and density of dopaminergic neurons was also assessed in the ventral tegmental area (VTA) across the genotypes. COMT genotype × THC treatment interactions were observed for: (1) dopaminergic cell size in the VTA, (2) CB1R protein expression in the HPC, and (3) parvalbumin (PV) cell size in the PFC. No effects of adolescent THC treatment were observed for PV and dopaminergic cell density across the COMT genotypes. COMT genotype modulates the effects of chronic THC administration during adolescence on indices of neurotransmitter function in the brain. These findings illuminate how COMT deletion and adolescent cannabis use can interact to modulate the function of neurotransmitters systems implicated in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 474 | FASEB J. 2012 Jun 26: 2712-8 |
| PMID | 22426120 |
| Title | Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. |
| Abstract | Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia's nonmendelian characteristics. To investigate this assumption, we examined genome-wide (global) and gene-specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia (P<2.0×10(-6)) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R(2)=0.11, ANOVA P<0.001). Specifically, haloperidol was associated with higher ("control-like") methylation (P=0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation (P=0.002). With regard to the gene-specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S-COMT was hypermethylated in patients with schizophrenia (P=0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA-methylation signatures show promise of serving as a schizophrenia biomarker in the future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 475 | Schizophr. Res. 2012 Feb 134: 211-8 |
| PMID | 22154595 |
| Title | Comparative gene expression study of the chronic exposure to clozapine and haloperidol in rat frontal cortex. |
| Abstract | Antipsychotic drugs (APDs) are effective in treating some of the positive and negative symptoms of schizophrenia. APDs take time to achieve a therapeutic effect which suggests that changes in gene expression are involved in their efficacy. We hypothesized that there would be altered expression of specific genes associated with the etiology or treatment of schizophrenia in frontal cortex of rats that received chronic treatment with a typical APD (haloperidol) vs. an atypical APD (clozapine). Rats were administered clozapine, haloperidol, or sterile saline intraperitoneally daily for 21days. Frontal cortices from clozapine-, haloperidol-, and saline-treated rats were dissected and subjected to microarray analysis. We observed a significant (1.5 fold, p<0.05) downregulation of 278 genes and upregulation of 73 genes in the clozapine-treated brains vs. controls and downregulation of 451 genes and upregulation of 115 genes in the haloperidol-treated brains vs. control. A total of 146 genes (130 downregulated and 16 upregulated) were significantly altered by both clozapine and haloperidol. These genes were classified by functional groups. qRT-PCR (quantitative real-time polymerase chain reaction) analysis verified the direction and magnitude of change for a group of nine genes significantly altered by clozapine and 11 genes significantly altered by haloperidol. Three genes verified by qRT-PCR were altered by both drugs: Bcl2-like 1 (Bcl2l1), catechol-O-methyltransferase (COMT), and opioid-binding protein/cell adhesion molecule-like (Opcml). Our results show that clozapine and haloperidol cause changes in levels of many important genes that may be involved in etiology and treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 476 | Psychol Med 2012 Mar 42: 607-16 |
| PMID | 21854684 |
| Title | Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. |
| Abstract | Candidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS). We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International schizophrenia Consortium (ISC). SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results. We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 477 | Neuropharmacology 2012 Mar 62: 1204-20 |
| PMID | 21557953 |
| Title | Mouse models of genetic effects on cognition: relevance to schizophrenia. |
| Abstract | Cognitive dysfunction is a core feature of schizophrenia. Growing evidence indicates that a wide variety of genetic mutations and polymorphisms impact cognition and may thus be implicated in various aspects of this mental disorder. Despite differences between human and rodent brain structure and function, genetic mouse models have contributed critical information about brain mechanisms involved in cognitive processes. Here, we summarize discoveries of genetic modifications in mice that impact cognition. Based on functional hypotheses, gene modifications within five model systems are described: 1) dopamine (D1, D2, D3, D4, D5, DAT, COMT, MAO); 2) glutamate (GluR-A, NR1, NR2A, NR2B, GRM2, GRM3, GLAST); 3) GABA (?(5), ?(2), ?(4), ?GABA(A), GABA(B(1)), GAT1); 4) acetylcholine (nAChR?2, ?7, CHRM1); and 5) calcium (CaMKII-?, neurogranin, CaMKK?, CaMKIV). We also consider other risk-associated genes for schizophrenia such as dysbindin (DTNBP1), neuregulin (NRG1), disrupted-in-schizophrenia1 (DISC1), reelin and proline dehydrogenase (PRODH). Because of the presumed importance of environmental factors, we further consider genetic modifications within the stress-sensitive systems of corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF) and the endocannabinoid systems. We highlight the missing information and limitations of cognitive assays in genetically modified mice models relevant to schizophrenia pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 478 | PLoS ONE 2012 -1 7: e32404 |
| PMID | 22384243 |
| Title | ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. |
| Abstract | ZNF804a was identified by a genome-wide association study (GWAS) in which a single nucleotide polymorphism (SNP rs1344706) in ZNF804a reached genome-wide statistical significance for association with a combined diagnosis of schizophrenia (SZ) and bipolar disorder. Although the molecular function of ZNF804a is unknown, the amino acid sequence is predicted to contain a C2H2-type zinc-finger domain and suggests ZNF804a plays a role in DNA binding and transcription. Here, we confirm that ZNF804a directly contributes to transcriptional control by regulating the expression of several SZ associated genes and directly interacts with chromatin proximal to the promoter regions of PRSS16 and COMT, the two genes we find upregulated by ZNF804a. Using immunochemistry we establish that ZNF804a is localized to the nucleus of rat neural progenitor cells in culture and in vivo. We demonstrate that expression of ZNF804a results in a significant increase in transcript levels of PRSS16 and COMT, relative to GFP transfected controls, and a statistically significant decrease in transcript levels of PDE4B and DRD2. Furthermore, we show using chromatin immunoprecipitation assays (ChIP) that both epitope-tagged and endogenous ZNF804a directly interacts with the promoter regions of PRSS16 and COMT, suggesting a direct upregulation of transcription by ZNF804a on the expression of these genes. These results are the first to confirm that ZNF804a regulates transcription levels of four SZ associated genes, and binds to chromatin proximal to promoters of two SZ genes. These results suggest a model where ZNF804a may modulate a transcriptional network of SZ associated genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 479 | Psychiatry Res 2012 Apr 196: 277-84 |
| PMID | 22377578 |
| Title | Preliminary structure and predictive value of attenuated negative symptoms in 22q11.2 deletion syndrome. |
| Abstract | Current research in schizophrenia suggests that negative symptoms cannot be considered a unitary construct and should be divided in two dimensions: lack of motivation and impoverishment of expression. In addition, negative symptoms are particularly related to decreased daily-life functioning. In the present study, we aimed to replicate these results in a sample of participants with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition associated with high risk of developing schizophrenia. We also expected to observe an association between the COMT Val/Met polymorphism and negative symptoms. We examined the factorial structure of negative symptoms in a sample of 47 individuals with 22q11DS using the Structured Interview for Prodromal Symptoms (SIPS) and the Positive and Negative Syndrome Scale (PANSS). We also performed stepwise regression analyses to investigate the associations between negative symptoms, adaptive skills and the COMT Val/Met polymorphism. Negative symptoms were explained by a two-factor solution, namely the "amotivation and social withdrawal" and the "emotional withdrawal and expression" dimensions. The motivational dimension was significantly associated with daily-life functioning. Met carriers were rated as experiencing significantly more symptoms of amotivation. The results are interpreted in the light of existing cognitive models in the field of motivation and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 480 | J Clin Psychopharmacol 2012 Apr 32: 261-5 |
| PMID | 22370993 |
| Title | Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics. |
| Abstract | Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject's mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (? = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (? = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate's role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 481 | Biol. Psychiatry 2012 Mar 71: 538-44 |
| PMID | 22364739 |
| Title | COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition. |
| Abstract | Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 482 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 370-5 |
| PMID | 22354729 |
| Title | Association of catechol-O-methyltransferase gene polymorphisms with schizophrenia and negative symptoms in a Chinese population. |
| Abstract | The gene encoding Catechol-O-methyltransferase (COMT), a dopamine catabolic enzyme, has been associated inconsistently with schizophrenia in spite of consistent evidence for dopaminergic dysfunction in the prefrontal cortex (PFC) of schizophrenia. Since one contribution to this inconsistency might be genetic heterogeneity, this study investigated whether the COMT gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese schizophrenic patients. We analyzed two polymorphisms (rs740603 and rs4818) of the COMT gene in a case-control study of 604 Han Chinese (284 patients and 320 controls). The patients' psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups. Quantitative trait analysis by the UNPHASED program showed that the rs740603 and rs740603(G)-rs4818(G) haplotypes were associated with negative symptoms in the schizophrenic patients, particularly among female patients. Thus, the COMT gene polymorphisms may not contribute to the susceptibility to schizophrenia, but may contribute to the negative symptoms of schizophrenia among Han Chinese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 483 | Behav. Neurosci. 2012 Feb 126: 209-15 |
| PMID | 22148860 |
| Title | Effects of the val(158)met catechol-O-methyltransferase gene polymorphism on olfactory processing in schizophrenia. |
| Abstract | The catechol-O-methyltransferase (COMT) val158met polymorphism has received attention in schizophrenia due to its role in prefrontal dopamine catabolism. Given the rich dopaminergic innervations of the olfactory bulb and the influence of dopamine on the transmission of olfactory signals, the authors examined the influence of COMT genotype status on the olfactory processing impairment observed in schizophrenia. The University of Pennsylvania Smell Identification Test was administered unirhinally to individuals with schizophrenia (n = 42) and a demographically matched sample of healthy controls (n = 30). Individuals were genotyped for the COMT val158met polymorphism. A statistically significant interaction of diagnosis and COMT genotype was observed, such that schizophrenia heterozygotes and Met homozygotes showed impaired odor identification accuracy relative to Val158 homozygotes. These findings could not be explained by factors such as antipsychotic medication status, clinical symptomatology, or demographic and illness characteristics. Notably, the schizophrenia Val158 homozygotes' odor identification performance was comparable to that of the control group. These data indicate that odor identification impairments observed in schizophrenia are influenced by the COMT val158met polymorphism. This relationship is consistent with specific dopaminergic modulation of primary olfactory sensory afferents, rather than a broader effect on cognitive processes. Future studies that examine the olfactory processing deficit in schizophrenia with respect to other olfactory measures and COMT haplotypes is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 484 | Acta Psychiatr Scand 2012 Mar 125: 247-56 |
| PMID | 22128864 |
| Title | Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress. |
| Abstract | A functional interaction between Catechol-O-Methyltransferase (COMT) Val158Met and methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to differentially affect cognition in patients with schizophrenia and healthy controls; the effect of COMT Val158Met × MTHFR interaction on resilience to stress in patients and controls remains to be examined. A total of 98 patients with non-affective psychotic disorder and 118 controls were genotyped for MTHFR C677T, MTHFR A1298C, and COMTVal158Met. Daily life reactivity to stress, modelled as the effect of daily life stress on psychotic experiences, was measured using the experience sampling method (ESM). The MTHFR C677T genotype moderated the interaction between COMT Val158Met genotype and stress in patients (P < 0.0001), but not in controls (P = 0.68). Further examination of this interaction revealed that in patients with the MTHFR 677 T-allele, COMT Met/Met individuals displayed the largest increases in psychotic symptoms in reaction to ESM stress [?(2)(2) = 29.51; P < 0.0001], whereas in patients with the MTHFR 677 C/C genotype no significant COMT Val158Met × ESM stress interaction was apparent [?(2)(2) = 3.65; P = 0.16]. No moderating effect of MTHFR A1298C was found. Stress reactivity associated with COMT Val158Met in patients with psychosis may crucially depend on MTHFR C677T genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 485 | Int. J. Neuropsychopharmacol. 2012 Oct 15: 1331-42 |
| PMID | 22074909 |
| Title | Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes. |
| Abstract | Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 486 | Psychopharmacology (Berl.) 2012 Apr 220: 647-72 |
| PMID | 22068459 |
| Title | Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models. |
| Abstract | Spontaneous (novel) object recognition (SOR) is one of the most widely used rodent behavioural tests. The opportunity for rapid data collection has made SOR a popular choice in studies that explore cognitive impairment in rodent models of schizophrenia, and that test the efficacy of drugs intended to reverse these deficits. We provide an overview of the many recent studies that have used SOR to explore the mnemonic effects of manipulation of the key transmitter systems relevant to schizophrenia-the dopamine, glutamate, GABA, acetylcholine, serotonin and cannabinoid systems-alone or in combination. We also review the use of SOR in studying memory in genetically modified mouse models of schizophrenia, as well as in neurodevelopmental and lesion models. We end by discussing the construct and predictive validity, and translational relevance, of SOR with respect to cognitive impairment in schizophrenia. Perturbation of the dopamine or glutamate systems can generate robust and reliable impairment in SOR. Impaired performance is also seen following antagonism of the muscarinic acetylcholine system, or exposure to cannabinoid agonists. Cognitive enhancement has been reported using alpha7-nicotinic acetylcholine receptor agonists and 5-HT(6) antagonists. Among non-pharmacological models, neonatal ventral hippocampal lesions and maternal immune activation can impair SOR, while mixed results have been obtained with mice carrying mutations in schizophrenia risk-associated genes, including neuregulin and COMT. While SOR is not without its limitations, the task represents a useful method for studying manipulations with relevance to cognitive impairment in schizophrenia, as well as the interactions between them. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 487 | J Clin Psychiatry 2012 Feb 73: 159-63 |
| PMID | 22053918 |
| Title | The relation of serotonin-related gene and COMT gene polymorphisms with criminal behavior in schizophrenic disorder. |
| Abstract | It has been suggested that patients with schizophrenia might be involved in criminal behavior, such as homicidal and violent behavior. However, the relationship between criminal behavior and genes in patients with schizophrenia has not been clearly elucidated. The objective of this study was to examine the relation between criminal behavior and serotonin-related gene or catechol-O-methyltransferase (COMT) gene polymorphisms in patients with schizophrenia. Serotonin-related and COMT polymorphic markers were assessed by using single nucleotide polymorphism (SNP) genotyping. Ninety-nine crime-related inpatients with schizophrenia (57 homicidal and 42 nonhomicidal violent) and 133 healthy subjects were enrolled between October 2005 and May 2008. Diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. The genotype frequencies of tryptophan hydroxylase-1 (TPH1) A218C and COMT V158M were compared between groups. The TPH1 CC genotype had 2.7-fold higher odds of crime-related schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 2.69; 95% CI, 1.22 - 5.91; P = .01). In addition, the TPH1 CC genotype had 3.4-fold higher odds of homicidal schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 3.38; 95% CI, 1.40 - 8.18; P = .007). However, no significant differences were found in the frequencies of genotype of COMT polymorphism between criminal schizophrenics and healthy subjects, nor were any significant differences found between nonhomicidal schizophrenics and healthy subjects. These results indicate that the TPH1 CC recessive genotype is likely to be a genetic risk factor for criminal behavior, especially homicidal behavior in patients with schizophrenia. However, COMT gene polymorphisms were not associated with criminal behavior in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 488 | Clin. Biochem. 2012 Jul 45: 787-92 |
| PMID | 22560999 |
| Title | Impact of catechol-o-methyltransferase polymorphisms on risperidone treatment for schizophrenia and its potential clinical significance. |
| Abstract | The main aim was to study the effects of COMT polymorphisms on response of risperidone treatment for schizophrenia and investigate the correlation between memory function of schizophrenia patients and COMT polymorphisms. Subjects were 83 schizophrenic patients who were antipsychotic drug free at the initiation of this study. Peripheral blood samples were obtained to identify COMT polymorphisms by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Clinical Global Impressions (CGI), Positive and Negative Syndrome Scale (PANSS) and Wechsler Memory Scale (WMS) test were used to assess the effect of risperidone treatment. The Val/Met carriers showed a significant increase in change of P300 during treatment (P=0.032). Association of Val/Met carriers performed better than other genotypes (P=0.028). The mean plasma concentration of prolactin of Val/Val carriers was significantly lower (P=0.017). The COMT polymorphisms may be a potential biomarker for clinical risperidone treatment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 489 | Scientifica (Cairo) 2012 -1 2012: 560514 |
| PMID | 24278715 |
| Title | The Association between COMT, BDNF, and NRG1 and Premorbid Social Functioning in Patients with Psychosis, Their Relatives, and Controls. |
| Abstract | We investigated the influences of putative candidate genes for psychosis on premorbid social adjustment and on premorbid schizoid-schizotypal traits. A family-based sample was used including 177 patients with schizophrenia or bipolar I disorder with a history of psychotic symptoms, 86 of their unaffected relatives, and 116 unrelated healthy controls. Association analyses on the combined sample were conducted using the Statistical Analysis for Genetic Epidemiology software (SAGE) and adjusting for age, sex, clinical group, and the family-based nature of the data. The COMT Val(158)Met and BDNF Val(66)Met polymorphisms showed no evidence of association with either phenotype. The SNP rs221533 of the NRG1 gene was significantly associated with premorbid adjustment in adolescence with TT homozygous subjects having a poorer performance than C allele carriers. In the context of neurodevelopmental disorders such as schizophrenia and other psychoses, this finding is plausible; however, it is preliminary and requires replication in an independent sample. In a broader sense, the use of intermediate quantitative phenotypes such as the ones presented in this study may be of help to understand the mechanism of action of genetic risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 490 | Psychiatr. Genet. 2012 Dec 22: 298-9 |
| PMID | 22935916 |
| Title | Association between a COMT polymorphism and clinical response to risperidone treatment: a pharmacogenetic study. |
| Abstract | A total of 130 Chinese schizophrenic patients (45 male, 85 female) were enrolled in the study. Clinical efficacy was determined using Brief Psychiatric Rating Scale (BPRS) scores. We genotyped 10 single-nucleotide polymorphisms (SNPs) of the catechol-O-methyl transferase gene (COMT) in our patients and re-examined them for association with changes in BPRS scores after 8 weeks of risperidone monotherapy. COMT is one of the genes that confer susceptibility to schizophrenia, both because of its role in neurotransmitter metabolism and because of its location in the high-risk schizophrenia-related region 22q11. Recent studies also found that COMT functional polymorphisms influenced individual response to antipsychotic medication. Our aim in this study was to explore the influence of COMT polymorphisms on pharmacological response to risperidone in the Chinese population. Statistical analysis revealed a significant association between an upstream COMT SNP, rs9606186, and scores reduction of BPRS in all patients and in the male subgroup but not in the female subgroup (allele analysis: P=0.055 for all, P=0.012 for male patients; genotype analysis: P=0.046 for all, P=0.020 for male patients, uncorrected, odds ratio=3.95). The COMT gene polymorphism, SNP rs9606186, is associated with risperidone therapy efficiency in the Chinese population. This association exhibited a sexually dimorphic difference, which may shed light on the genetics of COMT and its enzymatic sex-dependent mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 491 | Pharmacol Rep 2012 -1 64: 528-35 |
| PMID | 22814006 |
| Title | Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. |
| Abstract | Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 492 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 370-5 |
| PMID | 22354729 |
| Title | Association of catechol-O-methyltransferase gene polymorphisms with schizophrenia and negative symptoms in a Chinese population. |
| Abstract | The gene encoding Catechol-O-methyltransferase (COMT), a dopamine catabolic enzyme, has been associated inconsistently with schizophrenia in spite of consistent evidence for dopaminergic dysfunction in the prefrontal cortex (PFC) of schizophrenia. Since one contribution to this inconsistency might be genetic heterogeneity, this study investigated whether the COMT gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese schizophrenic patients. We analyzed two polymorphisms (rs740603 and rs4818) of the COMT gene in a case-control study of 604 Han Chinese (284 patients and 320 controls). The patients' psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups. Quantitative trait analysis by the UNPHASED program showed that the rs740603 and rs740603(G)-rs4818(G) haplotypes were associated with negative symptoms in the schizophrenic patients, particularly among female patients. Thus, the COMT gene polymorphisms may not contribute to the susceptibility to schizophrenia, but may contribute to the negative symptoms of schizophrenia among Han Chinese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 493 | J Clin Psychiatry 2012 Feb 73: 159-63 |
| PMID | 22053918 |
| Title | The relation of serotonin-related gene and COMT gene polymorphisms with criminal behavior in schizophrenic disorder. |
| Abstract | It has been suggested that patients with schizophrenia might be involved in criminal behavior, such as homicidal and violent behavior. However, the relationship between criminal behavior and genes in patients with schizophrenia has not been clearly elucidated. The objective of this study was to examine the relation between criminal behavior and serotonin-related gene or catechol-O-methyltransferase (COMT) gene polymorphisms in patients with schizophrenia. Serotonin-related and COMT polymorphic markers were assessed by using single nucleotide polymorphism (SNP) genotyping. Ninety-nine crime-related inpatients with schizophrenia (57 homicidal and 42 nonhomicidal violent) and 133 healthy subjects were enrolled between October 2005 and May 2008. Diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. The genotype frequencies of tryptophan hydroxylase-1 (TPH1) A218C and COMT V158M were compared between groups. The TPH1 CC genotype had 2.7-fold higher odds of crime-related schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 2.69; 95% CI, 1.22 - 5.91; P = .01). In addition, the TPH1 CC genotype had 3.4-fold higher odds of homicidal schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 3.38; 95% CI, 1.40 - 8.18; P = .007). However, no significant differences were found in the frequencies of genotype of COMT polymorphism between criminal schizophrenics and healthy subjects, nor were any significant differences found between nonhomicidal schizophrenics and healthy subjects. These results indicate that the TPH1 CC recessive genotype is likely to be a genetic risk factor for criminal behavior, especially homicidal behavior in patients with schizophrenia. However, COMT gene polymorphisms were not associated with criminal behavior in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 494 | CNS Neurol Disord Drug Targets 2012 May 11: 299-305 |
| PMID | 22483294 |
| Title | Catechol-o-methyltransferase and Alzheimer's disease: a review of biological and genetic findings. |
| Abstract | Alzheimer's disease (AD) is the leading cause of dementia worldwide and is associated with a marked individual, familial and social burden. Catechol-O-mehyltransferase (COMT) is surfacing with a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters and estrogen. COMT gene regulates dopamine levels in the prefrontal cortex which are involved in working memory and executive functioning. Impaired executive functioning is reported in a subgroup of AD patients and is associated with a more severe disorder, a more rapid disease progression and a shorter survival. The COMT rs4680 gene polymorphism has been investigated as a susceptibility factor for AD. No statistically significant results were found in meta-analysis but one study reported that the rs4680 Val allele was associated with AD-related psychosis. The COMT rs4680 polymorphism was also found to modulate declarative episodic memory in normal people and schizophrenic subjects. COMT inhibitors, that are adjunctive drugs in Parkinson's disease treatment, lower homocysteine levels and improve executive memory processes in normal subjects. A preliminary study, which needs replication, demonstrates that COMT inhibitors block beta-amyloid fibrils in vitro. Taken together, these findings suggest that research should focus on the role of COMT in AD pathogenesis and on the feasibility of targeting COMT activity in AD treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 495 | J Clin Psychiatry 2012 Feb 73: 159-63 |
| PMID | 22053918 |
| Title | The relation of serotonin-related gene and COMT gene polymorphisms with criminal behavior in schizophrenic disorder. |
| Abstract | It has been suggested that patients with schizophrenia might be involved in criminal behavior, such as homicidal and violent behavior. However, the relationship between criminal behavior and genes in patients with schizophrenia has not been clearly elucidated. The objective of this study was to examine the relation between criminal behavior and serotonin-related gene or catechol-O-methyltransferase (COMT) gene polymorphisms in patients with schizophrenia. Serotonin-related and COMT polymorphic markers were assessed by using single nucleotide polymorphism (SNP) genotyping. Ninety-nine crime-related inpatients with schizophrenia (57 homicidal and 42 nonhomicidal violent) and 133 healthy subjects were enrolled between October 2005 and May 2008. Diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. The genotype frequencies of tryptophan hydroxylase-1 (TPH1) A218C and COMT V158M were compared between groups. The TPH1 CC genotype had 2.7-fold higher odds of crime-related schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 2.69; 95% CI, 1.22 - 5.91; P = .01). In addition, the TPH1 CC genotype had 3.4-fold higher odds of homicidal schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 3.38; 95% CI, 1.40 - 8.18; P = .007). However, no significant differences were found in the frequencies of genotype of COMT polymorphism between criminal schizophrenics and healthy subjects, nor were any significant differences found between nonhomicidal schizophrenics and healthy subjects. These results indicate that the TPH1 CC recessive genotype is likely to be a genetic risk factor for criminal behavior, especially homicidal behavior in patients with schizophrenia. However, COMT gene polymorphisms were not associated with criminal behavior in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 496 | Schizophr. Res. 2013 Dec 151: 289-90 |
| PMID | 24268936 |
| Title | Age at onset of schizophrenia: cannabis, COMT gene, and their interactions. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 497 | Schizophr. Res. 2013 Nov 150: 602-3 |
| PMID | 24084577 |
| Title | Effect of COMT Val(158)Met genotype on nicotine withdrawal-related cognitive dysfunction in smokers with and without schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 498 | Clin Ter 2013 -1 164: e319-24 |
| PMID | 24045531 |
| Title | [Genetics and epigenetics of schizophrenia]. |
| Abstract | schizophrenia is a severe psychiatric disorder with an estimate prevalence of 0.3-0.7%. Studies on family aggregation showed a higher incidence of disease among family members of affected people. This observation lead to formulate the hypothesis that schizophrenia could be inheritable, but twin studies have shown a concordance of disease between monozygotic twins only of 50%, indicating the concomitant role of environmental factors in the pathogenesis of schizophrenia. Researches in molecular biology field have allowed the identification of genes that confer susceptibility to schizophrenia on chromosomes 1, 2, 3, 5, 6, 8, 10, 11, 13, 14, 20 and 22. Epigenetic modifications of gene expression, that not involve the primary DNA sequence, may also predispose to schizophrenia, in particular the methylation of genes involved in neurotransmission (RELN, GAD1, MARLIN-1, and NR3B GRIA2, VGLUT1 and 2, 5HT2a, COMT and BDNF), the histone modifications and the action of non-coding RNAs. This review deals with the results of a bibliographic retrieval on PubMed, carried out, using the key words: schizophrenia, genetics, epigenetics. From the epitomized results it can be derived that schizophrenia seems to be a multifactorial disease. Environmental factors, that can cause epigenetic modifications, are important in its pathogenesis, acting on a biological inheritable vulnerability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 499 | Cent Nerv Syst Agents Med Chem 2013 -1 13: 166-94 |
| PMID | 24450388 |
| Title | Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders. |
| Abstract | Catechol-O-methyltransferase (COMT) is the enzyme which catalyzes the transfer of a methyl group from S-adenosylmethionine to catechols and catecholamines, like the neurotransmitters dopamine, epinephrine and norepinephrine. COMT has implications in many neurological and psychiatric disorders like schizophrenia, Parkinson's disease (PD), bipolar disorders, etc. and therefore, it serves as an important drug target. Since its characterization in 1957, many inhibitors were designed where the first generation inhibitors were found to be highly toxic, short acting and had poor bioavailability. Currently, two of the second generation inhibitors, tolcapone and entacapone have been used for treatment of PD but are associated with various dopaminergic and gastro-intestinal side-effects. There have been several approaches for the design of novel COMT inhibitors with a good and safe therapeutic profile. The focus of this article is to review the current knowledge on COMT and the role of COMT inhibitors in the treatment of neurological disorders. The inhibitors have been classified into six different classes based on the structural framework. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on new generation of inhibitors till date. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 500 | Schizophr. Res. 2013 Dec 151: 91-6 |
| PMID | 24119464 |
| Title | Sequential processing deficits in schizophrenia: relationship to neuropsychology and genetics. |
| Abstract | Utilizing a combination of neuropsychological and cognitive neuroscience approaches may be essential for characterizing cognitive deficits in schizophrenia and eventually assessing cognitive outcomes. This study was designed to compare the stability of select exemplars for these approaches and their correlations in schizophrenia patients with stable treatment and clinical profiles. Reliability estimates for serial order processing were comparable to neuropsychological measures and indicate that experimental serial order processing measures may be less susceptible to practice effects than traditional neuropsychological measures. Correlations were moderate and consistent with a global cognitive factor. Exploratory analyses indicated a potentially critical role of the Met allele of the Catechol-O-methyltransferase (COMT) Val158Met polymorphism in externally paced sequential recall. Experimental measures of serial order processing may reflect frontostriatal dysfunction and be a useful supplement to large neuropsychological batteries. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 501 | Zh Nevrol Psikhiatr Im S S Korsakova 2013 -1 113: 50-6 |
| PMID | 24077552 |
| Title | [The association of COMT and DRD2 gene polymorphisms with a cognitive ability to understand others in schizophrenic patients]. |
| Abstract | To evaluate a role of dopamine transmission in the theory of mind (ToM) dysfunction in schizophrenia, authors studied the association of ToM with COMT and DRD2 gene polymorphisms in 209 patients with schizophrenia and 172 healthy people. All subjects performed second-order false belief (FB2) and faux pas stories. The association between the COMT Val158Met polymorphism and performance on FB2 was found. The association was sex-specific. The worse performance was associated with a Met allele in female patients and with the ValVal genotype in male ones. A correlation analysis of the COMT Val158Met polymorphism, performance on FB2 task, neurocognitive and clinical symptoms suggests that in female patients the association was modified, in part, by the higher stress sensitivity caused by the severity of clinical symptoms and its consequences for cognitive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 502 | J. Mol. Graph. Model. 2013 Feb 39: 145-64 |
| PMID | 23280413 |
| Title | Pharmacophore modeling and virtual screening studies to design potential COMT inhibitors as new leads. |
| Abstract | Catechol-O-methyltransferase (COMT) catalyzes the methylation of catecholamines, including neurotransmitters like dopamine, epinephrine and norepinephrine, leading to their degradation. COMT has been a subject of study for its implications in numerous neurological disorders like Parkinson's disease (PD), schizophrenia, and depression. The COMT gene is associated with many allelic variants, the Val108Met polymorphism being the most clinically significant. Availability of crystal structure of both 108V and 108M forms of human soluble-COMT (S-COMT) facilitated us to use structure-based virtual screening approach to obtain new hits by screening a library of CNS permeable compounds from ZINC database. In this study, E-pharmacophore was also used to generate pharmacophore models based on a series of known COMT inhibitors. A five-point pharmacophore model consisting of one hydrogen-bond acceptor (A), two hydrogen bond donors (D), and two aromatic rings (R) was generated for both the polymorphic forms of COMT. These models were then used for filtering ZINC-CNS permeable library to obtain new hits. Physicochemical properties were also calculated for all the hits obtained from both the approaches for favorable ADME properties. These identified hits maybe of interest for further structural optimization and biological evaluation assays. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 503 | Neuropharmacology 2013 Jan 64: 264-7 |
| PMID | 22992330 |
| Title | Genetic correlate of cognitive training response in schizophrenia. |
| Abstract | Intensive computerized auditory training results in improved cognition for schizophrenia patients, but participants show variation in their cognitive gains and the biological factors that affect the response to training are unknown. Single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been related to cognitive function. Here we asked if functional variation in this gene has an impact on the response of schizophrenia patients to cognitive training. We genotyped 48 schizophrenia patients who completed 50 h of computerized cognitive training and analyzed the association between DNA variants in the COMT gene and the improvement in global cognition. Although conventional analyses did not reveal any significant associations, a set-based analysis examining the aggregate effect of common variation in the COMT gene (42 SNPs) suggested association with improvement in global cognition. Eight SNPs, mostly located in the 3' end of the COMT gene, were nominally associated with improvement in cognition. These data suggest that genotype influences the response to intensive cognitive training in schizophrenia, and may indicate that cognitive training regimens need to be personalized to the underlying biosignatures of each individual patient. This article is part of a Special Issue entitled 'Cognitive Enhancers'. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 504 | Neuropharmacology 2013 Dec 75: 233-45 |
| PMID | 23958448 |
| Title | Active DNA demethylation in post-mitotic neurons: a reason for optimism. |
| Abstract | Over the last several years proteins involved in base excision repair (BER) have been implicated in active DNA demethylation. We review the literature supporting BER as a means of active DNA demethylation, and explain how the various components function and cooperate to remove the potentially most enduring means of epigenetic gene regulation. Recent evidence indicates that the same pathways implicated during periods of widespread DNA demethylation, such as the erasure of methyl marks in the paternal pronucleus soon after fertilization, are operational in post-mitotic neurons. Neuronal functional identities, defined here as the result of a combination of neuronal subtype, location, and synaptic connections are largely maintained through DNA methylation. Chronic mental illnesses, such as schizophrenia, may be the result of both altered neurotransmitter levels and neurons that have assumed dysfunctional neuronal identities. A limitation of most current psychopharmacological agents is their focus on the former, while not addressing the more profound latter pathophysiological process. Previously, it was believed that active DNA demethylation in post-mitotic neurons was rare if not impossible. If this were the case, then reversing the factors that maintain neuronal identity, would be highly unlikely. The emergence of an active DNA demethylation pathway in the brain is a reason for great optimism in psychiatry as it provides a means by which previously pathological neurons may be reprogrammed to serve a more favorable role. Agents targeting epigenetic processes have shown much promise in this regard, and may lead to substantial gains over traditional pharmacological approaches. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 505 | Neuro Endocrinol. Lett. 2013 -1 34: 792-7 |
| PMID | 24522021 |
| Title | Interactive effect of MTHFR and ADRA2A gene polymorphisms on pathogenesis of schizophrenia. |
| Abstract | Increasing evidences support the importance of epigenetic control in schizophrenia pathogenesis. One of the enzymes involved in DNA methylation process through homocysteine metabolism is methylenetetrahydrofolate reductase (MTHFR). The most extensively studied variant in the MTHFR gene is the C677T polymorphism, resulting in reduced enzyme activity and elevated homocysteine level. In sample of 192 schizophrenics and 213 healthy controls an increasing risk of schizophrenia associated with MTHFR 677 CT+TT genotype was found (OR=1.6, p=0.021). Association was also evaluated by considering the C677T polymorphism as an interaction with COMT Val158Met and ADRA2A C-1291G polymorphisms previously associated with schizophrenia risk using a logistic regression analysis. Previous studies of MTHFR*COMT (C677T*Val158Met) interaction in relation to schizophrenia resulted in inconsistent results. In our sample this interaction did not significantly differ between schizophrenics and control subjects. On the other hand analysis of MTHFR*ADRA2A (C677T*C-1291G) interaction revealed significant association between ADRA2A CC+CG genotype in the MTHFR TC+TT carriers (p=0.008). Our results support role of noradrenergic functions as well as previously proposed role of epigenetic control in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to prove our results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 506 | World J Psychiatry 2013 Sep 3: 57-61 |
| PMID | 24255876 |
| Title | New findings in the genetics of schizophrenia. |
| Abstract | New findings in schizophrenia genetics are based on genome-wide association studies (GWAS), research into DNA copy number variations (CNVs), and endophenotypes. More than 70 genes have recently been suspected to be involved in the genetic background of schizophrenia based on the GWAS´s results. They are typically related to neurodevelopment/neuroplasticity, immunology and neuroendocrinology. Nevertheless, for many detected genes their possible relationship to schizophrenia etiopathogenesis is still unknown. The CNVs at genome loci 1q21.1 (candidate gene e.g., PRKAB2), 2p16.3 (candidate gene e.g., NRXN1), 3q29 (candidate genes e.g., BDH1, DLG1, PAK2 or TFRC), 15q11.2 (candidate gene e.g., CYFIP1), 15q13.3 (candidate gene e.g., CHRNA7), 16p13.1 (candidate genes e.g.,NTAN1 or NDE1) and 22q11.2 (candidate genes e.g., COMT, GSTT2 or PRODH) were associated with schizophrenia most frequently. Genetic research of schizophrenia endophenotypes, usually neurophysiological, neuromotoric, neurocognitive, neuroanatomical, neurological or personality-related, will help us to discover the role of relevant genes in the pathogenesis of schizophrenia. It is also necessary to integrate knowledge from other research platforms in schizophrenia, like epigenetics, studies of gene-environment interactions, transcriptomics, proteomics, metabolomics, neuroimaging and psychopathology. A better knowledge of the genetic background of schizophrenia can lead to changes in the treatment, prevention and genetic counselling. It may also reduce stigma in this severe mental disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 507 | Pharmacol Rep 2013 -1 65: 1185-93 |
| PMID | 24399714 |
| Title | BDNF rs 6265 polymorphism and COMT rs 4680 polymorphism in deficit schizophrenia in Polish sample. |
| Abstract | Deficit schizophrenia (DS) is distinguished from the group of schizophrenic psychoses based on the presence of primary negative symptoms. It differs from nondeficit (NDS) forms of schizophrenia in dimensions such as risk factors, family history, course of illness and neurobiological differences. The aim of the study was assessment of a potential association of the investigated polymorphisms of the brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes with the deficit syndrome in schizophrenia. A cohort of 200 patients with schizophrenia (81 DS and 119 NDS subjects) and a group of 100 control subjects matched for ethnicity, sex and age were recruited. Somatic and psychometric assessment were conducted as well as structured interview about the influence of adverse biological, family and social factors. Genetic analysis of the BDNF (Val66Met) rs6265 and the COMT (Val158Met) rs4680 polymorphisms was performed. We found significant differences between DS and NDS in rs4680 COMT genotype distribution: more homozygous Val/Val were found (31 vs. 17%) in the NDS compared to the DS subgroup. No associations were found between the investigated polymorphisms of the BDNF gene and the presence of schizophrenia either in DS and NDS subgroups. The analysis of the COMT rs4680 polymorphism in the present DS and NDS study shows that some genetic factors may be relevant in analyzing the reasons for the differentiation of schizophrenic subtypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 508 | Ann Agric Environ Med 2013 -1 20: 77-81 |
| PMID | 23540216 |
| Title | The efficacy of cognitive rehabilitation with RehaCom programme in schizophrenia patients. The role of selected genetic polymorphisms in successful cognitive rehabilitation. |
| Abstract | schizophrenic patients present cognitive dysfunctions which are regarded to be one of endophenotypical markers predisposing to schizophrenia. Currently, schizophrenia can be treated as a neurodegenerative and neurodeveloping disease with genetic background. Assessment of the possible positive effect of neuropsychological rehabilitation in schizophrenia, in patients presenting cognitive dysfunctions. An additional aim was to verify the hypothesis that some genetic polymorphisms can be a prognostic factor for success in neuropsychological rehabilitation. 41 participants and 40 control subjects were randomly selected. Both groups had the diagnosis of paranoid schizophrenia. Cognitive functions were checked with the Wisconsin Card Sorting Test, Trail Making Test, and Stroop Test at the beginning and end of the experiment. In the research group, each patient trained with the rehabilitation programme RehaCom, whereas the control group did not receive such training. Genes COMT rs4680 and BDNF rs6265 were analysed in the genetic part of study. RehaCom procedures appear to be useful in the neuropsychological rehabilitation of cognitive dysfunctions in patients diagnosed with schizophrenia. The research group showed a moderate improvement in the training programmes. Analysis of parameters obtained in the neuropsychological tests showed a slight improvement in both groups. At the present time, analysis of the polymorphisms of genes cannot be treated as a prognostic factor for the success of neuropsychological rehabilitation because statistical analyses showed few dependences with little statistical significance. Cognitive rehabilitation produces moderate improvement in cognitive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 509 | Neuroscience 2013 Sep 249: 172-91 |
| PMID | 23298853 |
| Title | Stress and neurodevelopmental processes in the emergence of psychosis. |
| Abstract | The notion that stress plays a role in the etiology of psychotic disorders, especially schizophrenia, is longstanding. However, it is only in recent years that the potential neural mechanisms mediating this effect have come into sharper focus. The introduction of more sophisticated models of the interplay between psychosocial factors and brain function has expanded our opportunities for conceptualizing more detailed psychobiological models of stress in psychosis. Further, scientific advances in our understanding of adolescent brain development have shed light on a pivotal question that has challenged researchers; namely, why the first episode of psychosis typically occurs in late adolescence/young adulthood. In this paper, we begin by reviewing the evidence supporting associations between psychosocial stress and psychosis in diagnosed patients as well as individuals at clinical high risk for psychosis. We then discuss biological stress systems and examine changes that precede and follow psychosis onset. Next, research findings on structural and functional brain characteristics associated with psychosis are presented; these findings suggest that normal adolescent neuromaturational processes may go awry, thereby setting the stage for the emergence of psychotic syndromes. Finally, a model of neural mechanisms underlying the pathogenesis of psychosis is presented and directions for future research strategies are explored. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 510 | Psychiatry Res 2013 Oct 209: 431-8 |
| PMID | 23598060 |
| Title | Association study of polymorphisms in the alpha 7 nicotinic acetylcholine receptor subunit and catechol-o-methyl transferase genes with sensory gating in first-episode schizophrenia. |
| Abstract | The purpose of the current study was to explore the association of auditory P50 sensory gating (P50) and prepulse inhibition (PPI) of schizophrenia with polymorphisms in the CHRNA7 and COMT genes. One hundred and fourty patients with schizophrenia participated in this study. They were administered the tests P50 and PPI. Moreover, three single nucleotide polymorphisms (SNPs) (rs2337980, rs1909884 and rs883473) in CHRNA7 and three SNPs (rs4680, rs737865 and rs165599) in COMT were selected to be genotyped by polyacrylamide gel microarray techniques. P50 index showed significant reduction in S2 amplitude between wild-type and mutation groups in the COMT rs4680. S1 amplitude of mutation group in the COMT rs737865 was also lower compared to wild-type group. PPI index revealed a shorter pulse latency of mutation group in the rs4680. The suppression ratio of mutation group was lower in COMT rs165599. Negative findings were shown between comparisons in all the CHRNA7 SNPs. We find that P50 and PPI may be influenced by COMT rs4680 polymorphisms in schizophrenia; more excitingly, we find that P50 might be influenced by COMT rs737865 polymorphisms and PPI may be influenced by COMT rs165599 polymorphisms in schizophrenia, and their mutations are associated with the reduction of the risk of P50 or PPI defects in schizophrenia. Futher studies with a larger number of subjects are needed to verify the present findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 511 | PLoS ONE 2013 -1 8: e76763 |
| PMID | 24282499 |
| Title | Differential effects of the catechol-O-methyltransferase Val158Met genotype on the cognitive function of schizophrenia patients and healthy Japanese individuals. |
| Abstract | The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia. Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements. The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia. These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 512 | Behav. Brain Res. 2013 Nov 257: 118-28 |
| PMID | 24076151 |
| Title | Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats. |
| Abstract | Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of seven PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2-3 (SH) or in isolation (IR). PPI was measured early (d53) and later in adulthood (d74); LFPs were measured approximately on d66. Brains were processed for RT-PCR measures of mPFC and NAC expression of COMT, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Male IR rats exhibited PPI deficits, most pronounced at d53; male and female IR rats had significantly elevated startle magnitude on both test days. Gene expression levels were not significantly altered by IR. PPI levels (d53) were positively correlated with mPFC expression of several genes, and negatively correlated with NAC expression of several genes, in male IR but not SH rats. Late (P90) LFP amplitudes correlated significantly with expression levels of 6/7 mPFC genes in male rats, independent of rearing. After IR that disrupts early adult PPI in male BUF rats, expression levels of PPI- and SZ-associated genes in the mPFC correlate positively with PPI, and levels in the NAC correlate negatively with PPI. These results support the model that specific gene-behavior relationships moderate the impact of early-life experience on SZ-linked behavioral and neurophysiological markers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 513 | J Psychiatr Res 2013 Nov 47: 1615-22 |
| PMID | 23932573 |
| Title | Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort. |
| Abstract | Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have mostly been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. Therefore, these analyses were conducted in a north Indian sample. Indian SZ case-parent trios (n = 601 families); unscreened controls (n = 468) and an independent set of 118 trio families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n = 59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n = 260 cases and n = 302 parents). Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p < 0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540-rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and trio samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections. Suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 514 | J Psychiatr Res 2013 Nov 47: 1623-9 |
| PMID | 23910792 |
| Title | Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia - P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val(158)Met (rs4680) and PRODH Gln(19)Pro (rs2008720) and Arg(185)Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 515 | Neuropharmacology 2013 Dec 75: 38-46 |
| PMID | 23810830 |
| Title | Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats. |
| Abstract | After neonatal ventral hippocampal lesions (NVHLs), adult rats exhibit evidence of neural processing deficits relevant to schizophrenia, including reduced prepulse inhibition (PPI) of acoustic startle and impaired sensory processing. In intact rats, the regulation of PPI by the ventral hippocampus (VH) is mediated via interactions with medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked responses and expression of 7 schizophrenia-related genes in mPFC and NAC, in adult rats after sham- or real NVHLs. Male inbred Buffalo (BUF) rat pups (d7; n=36) received either vehicle or ibotenic acid infusion into the VH. PPI and auditory-evoked dentate gyrus local field potentials (LFPs) were measured on d56 and d66, respectively. Brains were processed for RT-PCR measures of mPFC and NAC COMT, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. NVHL rats exhibited significant deficits in PPI (p=0.005) and LFPs (p<0.015) proportional to lesion size. Sham vs. NVHL rats did not differ in gene expression levels in mPFC or NAC. As we previously reported, multiple gene expression levels were highly correlated within- (mean r's?0.5), but not across-brain regions (mean r's?0). However, for three genes--COMT, Slc1a2 and Ncam1--after NVHLs, expression levels became significantly correlated, or "coupled," across the mPFC and NAC (p's<0.03, 0.002 and 0.05, respectively), and the degree of "coupling" increased with VH lesion size. After NVHLs that disrupt PPI and auditory processing, specific gene expression levels suggest an abnormal functional coupling of the mPFC and NAC. This model of VH-mPFC-NAC network dysfunction after NVHLs may have implications for understanding the neural basis for PPI- and related sensory processing deficits in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 516 | J Psychiatr Res 2013 Jul 47: 872-9 |
| PMID | 23566421 |
| Title | Genetic variation in GAD1 is associated with cortical thickness in the parahippocampal gyrus. |
| Abstract | Patients with schizophrenia show widespread cortical thickness reductions throughout the brain. Likewise, reduced expression of the ?-Aminobutyric acid (GABA) synthesizing enzyme glutamic acid decarboxylase (GAD1) and a single nucleotide polymorphism (SNP) rs3749034 in the corresponding gene have been associated with schizophrenia. We tested whether this SNP is associated with reduced cortical thickness, an intermediate phenotype for schizophrenia. Because of the well known interactions between the GABAergic and dopaminergic systems, we examined whether associations between GAD1 rs3749034 and cortical thickness are modulated by the catechol-O-methyltransferase (COMT) Val158Met genotype. Structural MRI and genotype data was obtained from 94 healthy subjects enrolled in the Mind Clinical Imaging Consortium study to examine the relations between GAD1 genotype and cortical thickness. Our data show a robust reduction of cortical thickness in the left parahippocampal gyrus (PHG) in G allele homozygotes of GAD1 rs3749034. When we stratified our analyses according to the COMT Val158Met genotype, cortical thickness reductions of G allele homozygotes were only found in the presence of the Val allele. Genetic risk variants of schizophrenia in the GABAergic system might interact with the dopaminergic system and impact brain structure and functioning. Our findings point to the importance of the GABAergic system in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 517 | Neuroscience 2013 Jun 241: 147-56 |
| PMID | 23535252 |
| Title | Effects of COMT genotype on sensory gating and its modulation by nicotine: Differences in low and high P50 suppressors. |
| Abstract | Elevated smoking rates seen in schizophrenia populations may be an attempt to correct neuropathologies associated with deficient nicotinic acetylcholine receptors and/or dopaminergic systems using exogenous nicotine. However, nicotine's effects on cognitive processing and sensory gating have been shown to be baseline-dependent. Evidence of a restorative effect on sensory gating deficits by nicotine-like agonists has been demonstrated, however, its underlying mechanisms in the context of dopamine dysregulation are unclear. Catechol-O-methyltransferase (COMT), a key dopamine regulator in the brain, contains a co-dominant allele in which a valine-to-methionine substitution causes variations in enzymatic activity leading to reduced synaptic dopamine levels in the Val/Val genotype. Using a randomized, double-blind, placebo-controlled design with 57 non-smokers, this study examined the effects of COMT genotype on sensory gating and its modulation by nicotine in low vs. high suppressors. The results were consistent with the hypothesis that increased dopamine resulting from nicotine stimulation or Met allelic activity would benefit gating in low suppressors and impair gating in high suppressors, and that this gating improvement with nicotine would be more evident in Val carriers who were low suppressors, while the gating impairment would be more evident in Met carriers who were high suppressors. These findings reaffirm the importance of baseline-dependency and suggest a subtle relationship between COMT genotype and baseline-stratified levels of sensory gating, which may help to explain the variability of cognitive abilities in schizophrenia populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 518 | J Psychiatry Neurosci 2013 Nov 38: 366-80 |
| PMID | 23527885 |
| Title | COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation. |
| Abstract | Endophenotypes in genetic psychiatry may increase our understanding of the molecular mechanisms underlying disease risk and its manifestations. We sought to investigate the link between neuropsychological impairments and brain structural abnormalities associated with the COMT Val(158)Met polymorphism in patients with schizophrenia to improve understanding of the pathophysiology of this disorder. We performed a systematic review using studies identified in PubMed and MEDLINE (from the date of the first available article to July 2012). Our review examined evidence of an association between the COMT Val(158)Met polymorphism and both neuropsychological performance and brain structure in patients with psychosis, in their relatives and in healthy individuals (step 1). The review also explored whether the neuropsychological tasks and brain structures identified in step 1 met the criteria for an endophenotype (step 2). Then we evaluated evidence that the neuropsychological endophenotypes identified in step 2 are associated with the brain structure endophenotypes identified in that step (step 3). Finally, we propose a neurobiological interpretation for this evidence. A poorer performance on the n-back task and the Continuous Performance Test (CPT) and smaller temporal and frontal brain areas were associated with the COMT Val allele in patients with schizophrenia and their relatives and met most of the criteria for an endophenotype. It is possible that the COMT Val(158)Met polymorphism therefore contributes to the development of these neuropsychological and brain structural endophenotypes of schizophrenia, in which the prefrontal cortex may represent the neural substrate underlying both n-back and CPT performances. The association between a single genetic variant and an endophenotype does not necessarily imply a causal relationship between them. This evidence and the proposed interpretation contribute to explain, at least in part, the biological substrate of 4 important endophenotypes that characterize schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 519 | Front Hum Neurosci 2013 -1 7: 1 |
| PMID | 23355817 |
| Title | Dopaminergic foundations of schizotypy as measured by the German version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)-a suitable endophenotype of schizophrenia. |
| Abstract | The concept of schizotypy or "psychosis proneness" captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val(158)Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub-scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 520 | Neurosci. Lett. 2013 Mar 537: 17-22 |
| PMID | 23353103 |
| Title | COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study. |
| Abstract | The investigation of the catechol-O-methyltransferase (COMT-[rs4680]) and methylenetetrahydrofolate reductase (MTHFR-[rs1801133]) polymorphisms' interaction might shed light into the pathogenetic mechanisms of the cognitive dysfunction in schizophrenia. In an exploratory study, we hypothesized that the MTHFR 677T allele which has been related to a hypoactive MTHFR enzyme would augment the unfavorable effects of COMT Val158 homozygosity which has been associated with COMT enzyme hyperfunction. 90 schizophrenia patients and 55 healthy volunteers were assessed on psychomotor speed, pattern and spatial recognition memory (SRM), spatial working memory (SWM), attentional flexibility and planning (Stockings of Cambridge-SOC). IQ scores in a random subgroup of patients were also measured. A significant COMT×MTHFR interaction on SWM (p=0.048) and planning (p=0.026) was revealed in both groups. Among COMT-Val/Val participants, MTHFR-C/C made more SWM errors (p=0.033) and solved fewer SOC problems (p=0.025) than MTHFR-T carriers. In patients, there was a significant COMT×MTHFR interaction on full scale IQ (p=0.035): among COMT-Met carriers, MTHFR-T carriers performed significantly worse than MTHFR-C/C (p=0.021), which was driven by a COMT×MTHFR interaction involving performance IQ (p=0.047). In conclusion, COMT and MTHFR polymorphisms interacted on cognition, suggesting that the MTHFR enzyme activity might moderate the effects of the COMT enzyme. In contrast to our initial hypothesis, the MTHFR T-allele attenuated the cognitive effects of COMT Val homozygosity. In this preliminary study, we propose that dopaminergic and intracellular methylation mechanisms could interact on cognitive deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 521 | Mol Diagn Ther 2013 Feb 17: 21-30 |
| PMID | 23341251 |
| Title | Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy : is there a role for folate? |
| Abstract | In general, the presence of metabolic syndrome is associated with significant cardiovascular mortality and represents a growing public health concern in the USA. Patients with schizophrenia have a three times greater risk of death than the general population, with cardiovascular disease being the most common cause of this mortality. Use of atypical antipsychotics (AAPs) to treat schizophrenia contributes significantly to this cardiovascular risk. While several different clinical guidelines currently exist to monitor the metabolic consequences of AAP use, implementation is lacking. Because of under-monitoring of side effects and the lack of alternative treatment choices in schizophrenia, research has focused on identification of various biomarkers and pharmacogenomic targets to focus on the patients at greatest risk of metabolic syndrome, thus aiming to increase the efficacy and minimize the side effects of AAPs. This has led to several different lines of research. This review focuses on summarizing the differing metabolic syndrome criteria, monitoring guidelines for use of AAPs, and the role of folic acid as it relates to metabolic syndrome within the schizophrenia population. It concentrates not only on the pharmacogenomics of folic acid metabolism but also on its epigenetic interaction with the environment. From this work, genetic variation within both the methylenetetrahydrofolate reductase (MTHFR) gene and the catechol-O-methyltransferase (COMT) gene has been associated with an increased risk of metabolic syndrome in schizophrenia patients treated with AAPs. Furthermore, work on the combination of folate pharmacogenetics and epigenetics has uncovered relationships between methylation, schizophrenia disease, treatment type, and metabolic syndrome. Despite several areas of biomarker research into schizophrenia-related metabolic syndrome, translation into the clinical setting is still lacking, and further studies are needed to bridge this gap. In the future, folate supplementation may prove to be an easy and effective clinical tool for prevention and/or treatment of metabolic syndrome associated with AAP treatment, but clearly more research needs to be done in this area. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 522 | Eur Neuropsychopharmacol 2013 Oct 23: 1182-9 |
| PMID | 23332465 |
| Title | Polymorphisms in microRNA target sites influence susceptibility to schizophrenia by altering the binding of miRNAs to their targets. |
| Abstract | Single nucleotide polymorphisms (SNPs) in 3' untranslated regions (3' UTRs) of genes may affect miRNA binding to messenger RNA and contribute to the risk of disease. Whether the SNPs that modify miRNA binding in the 3' UTR are involved in schizophrenia-related genes remains unclear. We selected 803 SNPs from the 3' UTRs of 425 candidate genes for schizophrenia. The potential target SNPs were recognized by Gibbs free energy of miRNA binding. Some SNPs were associated in the literature with schizophrenia or other related neurological diseases. A case-control study of nine SNPs not previously reported as significant in any disease was carried out in a Chinese-Han cohort. We found that rs3219151 (C>T, GABRA6) showed significant decreased risk for schizophrenia (OR=0.8121, p=0.008, p(adjust)=0.03). Further, two putative target SNPs, rs165599 (COMT) and rs10759 (RGS4) reported in several references previously, were selected for analysis by luciferase assay to determine their modification to miRNA binding. We found that miR-124 showed significantly repressed 3' UTR binding to RGS4 mRNA from the rs10759-C allele (p<0.05). Our results suggest that rs3219151 of GABRA6 was associated significantly to decrease the risk of schizophrenia, rs10759 (RGS4) was possible to increase the risk of schizophrenia by miRNA altering the binding of miRNAs to their targets influencing susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 523 | In Silico Pharmacol 2013 -1 1: 15 |
| PMID | 25505659 |
| Title | Comparison of gene expression profiles in the blood, hippocampus and prefrontal cortex of rats. |
| Abstract | The comparability of gene expression between blood and brain tissues is a central issue in neuropsychiatric research where the analysis of molecular mechanisms in the brain is of high importance for the understanding of the diseases and the discovery of biomarkers. However, the accessibility of brain tissue is limited. Therefore, knowledge about how easily accessible peripheral tissue, e. g. blood, is comparable to and reflects gene expression of brain regions will help to advance neuropsychiatric research. Gene expression in the blood, hippocampus (HC) and prefrontal cortex (PFC) of genetically identical rats was compared using a genome-wide Affymetrix gene expression microarray covering 29,215 expressed genes. A total of 56.8% of 15,717 expressed genes were co-expressed in blood and at least one brain tissue, while 55.3% of all genes were co-expressed in all three tissues simultaneously. The overlapping genes included a set of genes of relevance to neuropsychiatric diseases, in particular bipolar disorder, schizophrenia and alcohol addiction. These genes included CLOCK, COMT, FAAH, NPY, NR3C1, NRGN, PBRM1, TCF4, and SYNE. This study provides baseline data on absolute gene expression and differences between gene expression in the blood, HC and PFC brain tissue of genetically identical rats. The present data represents a valuable resource for future studies as it might be used for first information on gene expression levels of genes of interest in blood and brain under baseline conditions. Limitations of our study comprise possible contamination of brain tissue with blood and the non-detection of genes with very low expression levels. Genes that are more highly expressed in the brain than in the blood are of particular interest since changes in their expression, e.g. due to disease status, or treatment, are likely to be detected in an experiment. In contrast, genes with higher expression in the blood than in the brain are less informative since their higher baseline levels could superimpose variation in brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 524 | Mol. Biol. Rep. 2013 Feb 40: 2053-8 |
| PMID | 23184041 |
| Title | No association between catechol-o-methyltransferase Val108/158Met polymorphism and schizophrenia or its clinical symptomatology in a Mexican population. |
| Abstract | The gene coding for catecol-o-methyltransferase (COMT), participant in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia. We determined the relation of the COMT Val108/158Met polymorphism with schizophrenia or its symptomatology (negative, disorganized and psychotic dimension). We conducted a case-control study comprising 186 patients with schizophrenia and 247 controls. The diagnosis of schizophrenia was established using the DSM-IV criteria for this illness. The clinical symptomatology was assessed through the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. No significant differences were found in the distribution of alleles (?2 = 0.01, df = 1, p = 0.90) or genotypes (?2 = 1.66, df = 2, p = 0.43) between schizophrenic patients and the control group. Multivariate analysis showed that the COMT Val108/158Met polymorphism has no influence in the clinical symptomatology of schizophrenia. Our results showed no association between COMT Val108/158Met and schizophrenia or evidence for an association between COMT and the clinical symptomatology of this illness. This suggests that the COMT gene may not contribute to the risk for schizophrenia among the Mexican population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 525 | Psychiatry Res 2013 Jul 208: 118-24 |
| PMID | 23102922 |
| Title | Impact of COMT genotype on cognition in schizophrenia spectrum patients and their relatives. |
| Abstract | Cognitive impairment in schizophrenia is a core feature and seems to be related mainly to dopaminergic dysfunction in the prefrontal cortex (PFC). The functional polymorphism Val158Met of the COMT (catechol-O-methyltransferase) gene could mediate the relationship between cognition and dopamine activity in PFC. The present study tested the influence of this polymorphism on the cognitive performance of schizophrenia spectrum patients and their relatives, using some subtests of the neuropsychological battery, the Measurement and Treatment Research to Improve Cognition in schizophrenia (MATRICS) Consensus Cognitive Battery, and evaluated the impact of this polymorphism on a specific prefrontal cognitive function using a cognitive neuroscience paradigm. A Group of 74 schizophrenia spectrum disorder patients, 48 relatives and 67 controls performed some subtests of the MATRICS Consensus Cognitive Battery. In addition, 40 schizophrenia spectrum disorder patients, 26 relatives and 63 controls performed the Dot Pattern Expectancy Task (DPX) to study context processing. For the neuropsychological battery, no differences in any of the cognitive domains were found according to genotype. The DPX task was sensitive to genotype effects in patients as well as in relatives. Context processing deficits in schizophrenia patients and their relatives may be mediated by COMT genotype. The influence of the COMT genotype on cognition is more relevant in specific cognitive tasks related to prefrontal function. These results should be replicated in larger samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 526 | Cogn Neuropsychiatry 2013 Jul 18: 257-83 |
| PMID | 23030509 |
| Title | COMT influences on prefrontal and striatal blood oxygenation level-dependent responses during working memory among individuals with schizophrenia, their siblings, and healthy controls. |
| Abstract | Recent theories have suggested that corticostriatal interactions may play an important part in mediating working memory demands and may impact clinical symptomology of schizophrenia. These effects are thought to occur through changes in dopamine signalling from the midbrain and via feedback from the frontal cortex. The catechol-O-methyltransferase (COMT) Val158Met polymorphism may prove useful for studying these effects in vivo. In this study, patients with schizophrenia, their well siblings, and healthy controls were genotyped and scanned using functional magnetic resonance imaging (fMRI) while they performed a working memory task. We found that patients and their siblings, but not controls, who were Val homozygotes displayed greater activity of the DLPFC, striatum, and the cerebellum during the task than respective Met carriers. We also found a relationship between striatal activity and negative symptoms for the Val homozygote group. Our findings support and extend previous studies of COMT effects on cognition and neural activity, and suggest that changes in dopamine availability may differentially impact corticostriatal functioning of individuals at risk for schizophrenia from those who are not. We also found some evidence supporting the proposed role of striatal dopamine signalling and clinical symptoms associated with anhedonia and apathy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 527 | Compr Psychiatry 2013 Feb 54: 181-6 |
| PMID | 22901597 |
| Title | Catechol-O-methyltransferase (COMT) genotype biases neural correlates of empathy and perceived personal distress in schizophrenia. |
| Abstract | The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism (rs4680) influences enzyme activity with valine (Val) allele associated with higher enzymatic activity. Several studies suggest that factors influencing dopaminergic transmission could control response to stressful situations. Empathy is an essential element of human behavior, requires the ability to adopt another person's perspective, and has been found to be dysfunctional in schizophrenia. Twenty-eight schizophrenic patients underwent functional magnetic resonance imaging performing an empathy task. Perceived empathy has been evaluated with the Interpersonal Reactivity Index. An effect of COMT on perceived distress subscale has been shown, with methionine (Met)/Met subjects reporting lower rates of stress compared with Val/Val. Moreover, imaging results showed an effect of genotype on empathy processing in the anterior cingulate with Val/Val subjects showing the lowest activation. This is the first study of the effect of rs4680 on interpersonal distress and neural correlates of empathy in schizophrenia. We found a decrease in neural responses in areas that ensure a cognitive control of emotion that is paralleled by perceived distress in interpersonal situation; this functional pattern seems to be influenced by rs4680 COMT polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 528 | Psychol Med 2013 Feb 43: 279-92 |
| PMID | 22617427 |
| Title | Interaction between catechol-O-methyltransferase (COMT) Val158Met genotype and genetic vulnerability to schizophrenia during explicit processing of aversive facial stimuli. |
| Abstract | Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing. A total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence. We found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype × diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing. Overall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 529 | Pharmacogenomics J. 2013 Jun 13: 264-71 |
| PMID | 22391769 |
| Title | The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia. |
| Abstract | The catechol-O-methyl transferase (COMT) 158Val/Met variant has been suggested to play a role in COMT function. Epigenetic regulation of COMT may further influence the prevalence of metabolic syndrome in these patient populations. This study examined the correlation between COMT promoter methylation and metabolic syndrome in schizophrenia patients receiving atypical antipsychotic (AAP) therapy. DNA was extracted from peripheral blood samples of schizophrenia subjects screened for metabolic syndrome. Pyrosequencing was used to analyze two methylation sites of the soluble COMT (COMT-s) promoter region. Associations between AAP use, lifestyle variables, metabolic syndrome and COMT genotype with peak methylation values were analyzed. Data are reported in 85 subjects. Methylation on CpG site 1 had a mean of 79.08% (±4.71) and it was 12.43% (±1.19) on site 2. COMT genotype proved to be an indicator of COMT methylation status on site 1 (F(2,?84)=5.78, P=0.0044) and site 2 (F(2,?84),=3.79, P=0.027). A significant negative correlation between physical activity and COMT promoter region methylation was found in Val/Val homozygous patients (site 1: P=0.013 and site 2: P=0.019). Those homozygous for Met/Met showed a positive correlation between promoter site methylation and physical activity (site 1: P=0.027, site 2: P=0.005), and between CpG site methylation and metabolic syndrome (site 1: P=0.002; site 2: P=0.001). The results of this study suggest that COMT promoter region methylation is largely influenced by COMT genotype and that physical activity plays a significant role in epigenetic modulation of COMT. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 530 | Schizophr Bull 2013 Mar 39: 330-8 |
| PMID | 22021659 |
| Title | Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia. |
| Abstract | Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 531 | Zh Nevrol Psikhiatr Im S S Korsakova 2013 -1 113: 50-6 |
| PMID | 24077552 |
| Title | [The association of COMT and DRD2 gene polymorphisms with a cognitive ability to understand others in schizophrenic patients]. |
| Abstract | To evaluate a role of dopamine transmission in the theory of mind (ToM) dysfunction in schizophrenia, authors studied the association of ToM with COMT and DRD2 gene polymorphisms in 209 patients with schizophrenia and 172 healthy people. All subjects performed second-order false belief (FB2) and faux pas stories. The association between the COMT Val158Met polymorphism and performance on FB2 was found. The association was sex-specific. The worse performance was associated with a Met allele in female patients and with the ValVal genotype in male ones. A correlation analysis of the COMT Val158Met polymorphism, performance on FB2 task, neurocognitive and clinical symptoms suggests that in female patients the association was modified, in part, by the higher stress sensitivity caused by the severity of clinical symptoms and its consequences for cognitive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 532 | Pharmacol Rep 2013 -1 65: 1185-93 |
| PMID | 24399714 |
| Title | BDNF rs 6265 polymorphism and COMT rs 4680 polymorphism in deficit schizophrenia in Polish sample. |
| Abstract | Deficit schizophrenia (DS) is distinguished from the group of schizophrenic psychoses based on the presence of primary negative symptoms. It differs from nondeficit (NDS) forms of schizophrenia in dimensions such as risk factors, family history, course of illness and neurobiological differences. The aim of the study was assessment of a potential association of the investigated polymorphisms of the brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes with the deficit syndrome in schizophrenia. A cohort of 200 patients with schizophrenia (81 DS and 119 NDS subjects) and a group of 100 control subjects matched for ethnicity, sex and age were recruited. Somatic and psychometric assessment were conducted as well as structured interview about the influence of adverse biological, family and social factors. Genetic analysis of the BDNF (Val66Met) rs6265 and the COMT (Val158Met) rs4680 polymorphisms was performed. We found significant differences between DS and NDS in rs4680 COMT genotype distribution: more homozygous Val/Val were found (31 vs. 17%) in the NDS compared to the DS subgroup. No associations were found between the investigated polymorphisms of the BDNF gene and the presence of schizophrenia either in DS and NDS subgroups. The analysis of the COMT rs4680 polymorphism in the present DS and NDS study shows that some genetic factors may be relevant in analyzing the reasons for the differentiation of schizophrenic subtypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 533 | Ann Agric Environ Med 2013 -1 20: 77-81 |
| PMID | 23540216 |
| Title | The efficacy of cognitive rehabilitation with RehaCom programme in schizophrenia patients. The role of selected genetic polymorphisms in successful cognitive rehabilitation. |
| Abstract | schizophrenic patients present cognitive dysfunctions which are regarded to be one of endophenotypical markers predisposing to schizophrenia. Currently, schizophrenia can be treated as a neurodegenerative and neurodeveloping disease with genetic background. Assessment of the possible positive effect of neuropsychological rehabilitation in schizophrenia, in patients presenting cognitive dysfunctions. An additional aim was to verify the hypothesis that some genetic polymorphisms can be a prognostic factor for success in neuropsychological rehabilitation. 41 participants and 40 control subjects were randomly selected. Both groups had the diagnosis of paranoid schizophrenia. Cognitive functions were checked with the Wisconsin Card Sorting Test, Trail Making Test, and Stroop Test at the beginning and end of the experiment. In the research group, each patient trained with the rehabilitation programme RehaCom, whereas the control group did not receive such training. Genes COMT rs4680 and BDNF rs6265 were analysed in the genetic part of study. RehaCom procedures appear to be useful in the neuropsychological rehabilitation of cognitive dysfunctions in patients diagnosed with schizophrenia. The research group showed a moderate improvement in the training programmes. Analysis of parameters obtained in the neuropsychological tests showed a slight improvement in both groups. At the present time, analysis of the polymorphisms of genes cannot be treated as a prognostic factor for the success of neuropsychological rehabilitation because statistical analyses showed few dependences with little statistical significance. Cognitive rehabilitation produces moderate improvement in cognitive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 534 | Mol. Biol. Rep. 2013 Feb 40: 2053-8 |
| PMID | 23184041 |
| Title | No association between catechol-o-methyltransferase Val108/158Met polymorphism and schizophrenia or its clinical symptomatology in a Mexican population. |
| Abstract | The gene coding for catecol-o-methyltransferase (COMT), participant in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia. We determined the relation of the COMT Val108/158Met polymorphism with schizophrenia or its symptomatology (negative, disorganized and psychotic dimension). We conducted a case-control study comprising 186 patients with schizophrenia and 247 controls. The diagnosis of schizophrenia was established using the DSM-IV criteria for this illness. The clinical symptomatology was assessed through the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. No significant differences were found in the distribution of alleles (?2 = 0.01, df = 1, p = 0.90) or genotypes (?2 = 1.66, df = 2, p = 0.43) between schizophrenic patients and the control group. Multivariate analysis showed that the COMT Val108/158Met polymorphism has no influence in the clinical symptomatology of schizophrenia. Our results showed no association between COMT Val108/158Met and schizophrenia or evidence for an association between COMT and the clinical symptomatology of this illness. This suggests that the COMT gene may not contribute to the risk for schizophrenia among the Mexican population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 535 | Compr Psychiatry 2013 Feb 54: 181-6 |
| PMID | 22901597 |
| Title | Catechol-O-methyltransferase (COMT) genotype biases neural correlates of empathy and perceived personal distress in schizophrenia. |
| Abstract | The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism (rs4680) influences enzyme activity with valine (Val) allele associated with higher enzymatic activity. Several studies suggest that factors influencing dopaminergic transmission could control response to stressful situations. Empathy is an essential element of human behavior, requires the ability to adopt another person's perspective, and has been found to be dysfunctional in schizophrenia. Twenty-eight schizophrenic patients underwent functional magnetic resonance imaging performing an empathy task. Perceived empathy has been evaluated with the Interpersonal Reactivity Index. An effect of COMT on perceived distress subscale has been shown, with methionine (Met)/Met subjects reporting lower rates of stress compared with Val/Val. Moreover, imaging results showed an effect of genotype on empathy processing in the anterior cingulate with Val/Val subjects showing the lowest activation. This is the first study of the effect of rs4680 on interpersonal distress and neural correlates of empathy in schizophrenia. We found a decrease in neural responses in areas that ensure a cognitive control of emotion that is paralleled by perceived distress in interpersonal situation; this functional pattern seems to be influenced by rs4680 COMT polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 536 | J Clin Psychopharmacol 2013 Oct 33: 593-9 |
| PMID | 23963056 |
| Title | The association study of polymorphisms in DAT, DRD2, and COMT genes and acute extrapyramidal adverse effects in male schizophrenic patients treated with haloperidol. |
| Abstract | Extrapyramidal symptoms (EPSs) are common adverse effects of antipsychotics. The development of acute EPSs could depend on the activity of dopaminergic system and its gene variants. The aim of this study was to determine the association between dopaminergic type 2 receptor (DRD2) dopamine transporter (SLC6A3) and catechol-O-methyltransferase (COMT) gene polymorphisms and acute EPSs in 240 male schizophrenic patients treated with haloperidol (15-mg/d) over a period of 2 weeks. Acute EPSs were assessed with Simpson-Angus Scale. Three dopaminergic gene polymorphisms, the DRD2 Taq1A, the SLC6A3 VNTR, and the COMT Val158Met, were determined. Extrapyramidal symptoms occurred in 116 (48.3%) of patients. Statistically significant associations were found for SLC6A3 VNTR and COMT Val158Met polymorphisms and EPS susceptibility. Patients with SLC6A3 9/10 genotype had almost twice the odds to develop EPSs compared with those with all other SLC6A3 genotypes (odds ratio, 1.9; 95% confidence interval, 1.13-3.30), and patients with COMT Val/Met genotype had 1.7 times greater odds to develop EPSs than those with all other COMT genotypes (odds ratio, 1.7; 95% confidence interval, 1.01-2.88). There was no statistically significant association between genotype and allele frequencies of DRD2, SLC6A3, or COMT polymorphisms and the development of particular EPSs.In conclusion, the results of the present study showed for the first time the association between acute haloperidol-induced EPSs and SLC6A3 VNTR and COMT Val158Met polymorphisms. Although the precise biological mechanisms underlying these findings are not yet understood, the results suggest that the dopaminergic gene variations could predict the vulnerability to the development of the acute EPSs in haloperidol-treated schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 537 | Neuro Endocrinol. Lett. 2013 -1 34: 792-7 |
| PMID | 24522021 |
| Title | Interactive effect of MTHFR and ADRA2A gene polymorphisms on pathogenesis of schizophrenia. |
| Abstract | Increasing evidences support the importance of epigenetic control in schizophrenia pathogenesis. One of the enzymes involved in DNA methylation process through homocysteine metabolism is methylenetetrahydrofolate reductase (MTHFR). The most extensively studied variant in the MTHFR gene is the C677T polymorphism, resulting in reduced enzyme activity and elevated homocysteine level. In sample of 192 schizophrenics and 213 healthy controls an increasing risk of schizophrenia associated with MTHFR 677 CT+TT genotype was found (OR=1.6, p=0.021). Association was also evaluated by considering the C677T polymorphism as an interaction with COMT Val158Met and ADRA2A C-1291G polymorphisms previously associated with schizophrenia risk using a logistic regression analysis. Previous studies of MTHFR*COMT (C677T*Val158Met) interaction in relation to schizophrenia resulted in inconsistent results. In our sample this interaction did not significantly differ between schizophrenics and control subjects. On the other hand analysis of MTHFR*ADRA2A (C677T*C-1291G) interaction revealed significant association between ADRA2A CC+CG genotype in the MTHFR TC+TT carriers (p=0.008). Our results support role of noradrenergic functions as well as previously proposed role of epigenetic control in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to prove our results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 538 | Front Hum Neurosci 2013 -1 7: 1 |
| PMID | 23355817 |
| Title | Dopaminergic foundations of schizotypy as measured by the German version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)-a suitable endophenotype of schizophrenia. |
| Abstract | The concept of schizotypy or "psychosis proneness" captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val(158)Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub-scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 539 | Front Psychiatry 2014 -1 5: 54 |
| PMID | 24904437 |
| Title | Gone to Pot - A Review of the Association between Cannabis and Psychosis. |
| Abstract | Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 540 | Psychiatr. Genet. 2014 Dec 24: 269-72 |
| PMID | 25325218 |
| Title | Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes. |
| Abstract | Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 541 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2014 Oct 31: 650-3 |
| PMID | 25297602 |
| Title | [Lack of association of COMT Val158Met polymorphism with attention and executive function in patients with schizophrenia]. |
| Abstract | To explore the association of a functional polymorphism Val158Met of COMT gene and attention and executive function in first-episode treatment-naive patients with schizophrenia and healthy controls. Trail making test (TMT) and clinical performances were evaluated in 103 first-episode treatment-naive patients with schizophrenia and 99 healthy controls. Polymorphism of COMT Val158Met was analyzed using polymerase chain reaction-restriction fragment length polymorphism method. A general linear model was used to investigate the effect of genotype subgroups on the attention and executive function. There was a significant difference between control subjects and patients with schizophrenia on the TMT-A and B. However, no significant difference among Val/Val, Val/Met and Met/Met on the TMT-A and B in control subjects and patients with schizophrenia was detected. The association among COMT Met variant and trail making testing (attention and executive function) has been replicated. However, no association of COMT Met variant with disruption of dopaminergic influence on neurocognitive function was detected. This may be due to the heterogeneity of population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 542 | Fa Yi Xue Za Zhi 2014 Jun 30: 197-201 |
| PMID | 25272876 |
| Title | [Progress on association between COMT gene and violence behavior in patients with schizophrenia]. |
| Abstract | The prevalence of violence behavior in patients with schizophrenia is higher than that in common population. Data suggest that genetic factors may play a substantial role for the etiology of the behavior. Among the particular gene polymorphisms that have been considered to be involved in violence behavior, the catechol-O-methyltransferase (COMT) gene had been the focus of recent research. This article reviews the association research between COMT gene and violence behavior in patients with schizophrenia in several aspects: SNP polymorphism of COMT Val158Met and COMT Ala72Ser, haplotype of COMT gene and DNA methylation of promoter region of COMT gene. The genetic research direction is presented for patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 543 | Schizophr. Res. 2014 Oct 159: 114-7 |
| PMID | 25139113 |
| Title | Effects of COMT genotype on cognitive ability and functional capacity in individuals with schizophrenia. |
| Abstract | Cognitive and functional impairments are core features of schizophrenia. This study examined the catechol-O-methyltransferase (COMT) genotype and its relationship to cognition and functional capacity in 188 individuals with schizophrenia or schizoaffective disorder. We found that in a dose-response fashion, individuals with more Met alleles performed significantly better on tests of learning/memory and abstraction. The effects of COMT genotype on cognition were modest, explaining about 3% of the variance in learning/memory and abstraction. Larger studies will be needed to examine the relationships between COMT and other genes and cognitive performance and everyday functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 544 | J. Med. Chem. 2014 Nov 57: 8692-717 |
| PMID | 25080080 |
| Title | Medicinal chemistry of catechol O-methyltransferase (COMT) inhibitors and their therapeutic utility. |
| Abstract | Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinson's disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 545 | Zh Nevrol Psikhiatr Im S S Korsakova 2014 -1 114: 42-8 |
| PMID | 24637816 |
| Title | [The effect of the serotonin transporter 5-HTTLPR polymorphism on the recognition of facial emotions in schizophrenia]. |
| Abstract | The 5-HTTLPR SLC6A4 and catechol-o-methyltransferase (COMT) Val158Met polymorphisms are reported to be associated with processing of facial expressions in general population. Impaired recognition of facial expressions that is characteristic of schizophrenia negatively impacts on the social adaptation of the patients. To search for molecular mechanisms of this deficit, we studied main and epistatic effects of 5-HTTLPR and Val158Met polymorphisms on the facial emotion recognition in patients with schizophrenia (n=299) and healthy controls (n=232). The 5-HTTLPR polymorphism was associated with the emotion recognition in patients. The ll-homozygotes recognized facial emotions significantly better compared to those with an s-allele (F=8.00; p=0.005). Although the recognition of facial emotions was correlated with negative symptoms, verbal learning and trait anxiety, these variables did not significantly modified the association. In both groups, no effect of the COMT on the recognition of facial emotions was found. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 546 | Eur. Psychiatry 2014 Jun 29: 304-6 |
| PMID | 24630741 |
| Title | Psychosis-proneness correlates with expression levels of dopaminergic genes. |
| Abstract | Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 547 | Transl Psychiatry 2014 -1 4: e356 |
| PMID | 24495967 |
| Title | Common polymorphisms in dopamine-related genes combine to produce a 'schizophrenia-like' prefrontal hypoactivity. |
| Abstract | Individual changes in dopamine-related genes influence prefrontal activity during cognitive-affective processes; however, the extent to which common genetic variations combine to influence prefrontal activity is unknown. We assessed catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) and dopamine D2 receptor (DRD2) G-T (rs2283265) single nucleotide polymorphisms and functional magnetic resonance imaging during an emotional response inhibition test in 43 healthy adults and 27 people with schizophrenia to determine the extent to which COMT Val108/158Met and DRD2 G-T polymorphisms combine to influence prefrontal response to cognitive-affective challenges. We found an increased number of cognitive-deficit risk alleles in these two dopamine-regulating genes predict reduced prefrontal activation during response inhibition in healthy adults, mimicking schizophrenia-like prefrontal hypoactivity. Our study provides evidence that functionally related genes can combine to produce a disease-like endophenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 548 | Int. J. Neuropsychopharmacol. 2014 Feb 17: 337-40 |
| PMID | 24229565 |
| Title | Entacapone augmentation of antipsychotic treatment in schizophrenic patients with negative symptoms; a double-blind placebo-controlled study. |
| Abstract | Negative symptoms in schizophrenia are associated with decreased dopaminergic activity in the prefrontal cortex (PFC). It is hypothesized that increasing dopamine levels would alleviate negative symptoms. Termination of dopamine activity in the PFC is mainly via catechol-O-methyl tranferase (COMT) activity. Hence, inhibition of COMT activity with entacapone should reverse PFC dopaminergic transmission. To assess the efficacy of entacapone addition to antipsychotic treatment in patients with residual schizophrenia, we conducted a double-blind, randomised, placebo-controlled study for 12 wk of treatment with entacapone or placebo. Clinical measures (PANSS, CGI and QLS) were obtained at baseline and at weeks 4, 8 and 12 and cognitive functions were assessed by the RBANSS. Significant improvement over time in PANSS and QLS scores was observed in both groups. However, entacapone did not demonstrate a beneficial effect compared to placebo. Therefore, this study does not support a therapeutic role for entacapone in residual schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 549 | Encephale 2014 Oct 40: 380-6 |
| PMID | 25127897 |
| Title | [Epigenetics of schizophrenia: a review]. |
| Abstract | schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders. The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter. We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post-translational histone modifications. First, in terms of epidemiology and transmission, the theoretical model of epigenetics applies to schizophrenia. Then, most environmental factors that have proved a link with this disease, may generate epigenetic mechanisms. Next, mutations have been found in regions implied in epigenetic mechanism among populations with schizophrenia. Some epigenetic alterations in DNA regions have been previously linked with neurodevelopmental abnormalities. In psychosis, some authors have found methylation differences in COMT gene, in reelin gene and in some genes implicated in dopaminergic, serotoninergic, GABAergic and glutamatergic pathways. Histone modifications have been described, in particular the H3L4 histone methylation. Finally, we tried to underline the difficulties in epigenetic research, notably in psychiatry, and the limits in this matter. The epigenetic field may explain a lot of questions around the physiopathology of the complex psychiatric disease that is schizophrenia. It may be a substratum to the prevailing hypothesis of gene x environment interaction. The research in the matter is definitely expanding. It justifies easily the need to improve the effort in the domain to overpass some limits inherent to the matter. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 550 | Acta Crystallogr. D Biol. Crystallogr. 2014 Aug 70: 2163-74 |
| PMID | 25084335 |
| Title | Mapping the conformational space accessible to catechol-O-methyltransferase. |
| Abstract | Methylation catalysed by catechol-O-methyltransferase (COMT) is the main pathway of catechol neurotransmitter deactivation in the prefrontal cortex. Low levels of this class of neurotransmitters are held to be causative of diseases such as schizophrenia, depression and Parkinson's disease. Inhibition of COMT may increase neurotransmitter levels, thus offering a route for treatment. Structure-based drug design hitherto seems to be based on the closed enzyme conformation. Here, a set of apo, semi-holo, holo and Michaelis form crystal structures are described that define the conformational space available to COMT and that include likely intermediates along the catalytic pathway. Domain swaps and sizeable loop movements around the active site testify to the flexibility of this enzyme, rendering COMT a difficult drug target. The low affinity of the co-substrate S-adenosylmethionine and the large conformational changes involved during catalysis highlight significant energetic investment to achieve the closed conformation. Since each conformation of COMT is a bona fide target for inhibitors, other states than the closed conformation may be promising to address. Crystallographic data for an alternative avenue of COMT inhibition, i.e. locking of the apo state by an inhibitor, are presented. The set of COMT structures may prove to be useful for the development of novel classes of inhibitors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 551 | Behav Brain Funct 2014 -1 10: 26 |
| PMID | 25073638 |
| Title | Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis. |
| Abstract | Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis. We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder. There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls. The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 552 | Neuropsychologia 2014 Aug 61: 45-55 |
| PMID | 24946318 |
| Title | Influence of the COMT val(108/158)met polymorphism on continuous performance task indices. |
| Abstract | The Continuous Performance Task (CPT) is a widely-used measure of sustained attention and impulsivity. Deficits in CPT performance have been found in several psychiatric disorders, such as Attention-Deficit/Hyperactivity Disorder (ADHD) and schizophrenia. Molecular genetic studies of CPT performance are currently limited and have generally revealed inconsistent findings. The current study tested the associations of the COMT val(108/158)met polymorphism with AX-CPT indices (i.e., omission and commission errors, d?, and ln?), as well as the variability of these indices across blocks, in a sample of clinic-referred and non-referred children (N=380). We found significant associations between COMT and variability in the Signal Detection Theory (SDT) indices d? and ln? across blocks, as well as a statistical trend for association between COMT and commission errors. Higher externalizing psychopathology was associated with general impairment on AX-CPT performance, and for some indices (i.e., d? variability and ln? variability) the effect of COMT was stronger at higher levels of psychopathology. Our findings support the role of COMT in components of CPT performance and highlight the potential utility of using SDT indices, particularly in relation to variability in performance. Moreover, our results suggest that for some indices the effect of COMT is stronger at higher levels of externalizing psychopathology. Our study yields some preliminary insights regarding the neurobiology of CPT performance, which may elucidate the mechanisms by which specific genes confer risk for various cognitive deficits, as well as relevant disorders characterized by these deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 553 | Psychiatry Res 2014 Oct 219: 261-7 |
| PMID | 24930580 |
| Title | Pharmacogenetics of adverse events in schizophrenia treatment: comparison study of ziprasidone, olanzapine and perazine. |
| Abstract | The primary aim of the present study was to assess the possible associations between dopaminergic, serotonergic, and glutamatergic system-related genes and adverse events after antipsychotic treatment in paranoid schizophrenia patients. The second aim of the study was to compare the intensity of these symptoms between atypical (ziprasidone and olanzapine) and typical (perazine) antipsychotic drugs. One-hundred and ninety-one Polish patients suffering from paranoid schizophrenia were genotyped for polymorphisms of DRD2, DAT1, COMT, MAOA, SERT, 5HT2A, and GRIK3. The patients were randomized to treatment with perazine, olanzapine or ziprasidone monotherapy for 3 months. The intensity of side effects (changes in body weights and extrapyramidal symptoms (EPS)) was measured at baseline and after 12 weeks of antipsychotic treatment. After 3 months of therapy, the weight increase was the greatest in the group treated with olanzapine and the least in the group treated with ziprasidone. None of the examined gene polymorphisms was associated with the body weight changes. Perazine treatment was associated with the significantly highest intensity of EPS. None of the examined polymorphisms was associated with the changes in extrapyramidal adverse events after antipsychotic treatment. The selected polymorphisms are not primarily involved in changes in body weights and EPS related to antipsychotic treatment in paranoid schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 554 | J Psychiatr Res 2014 Sep 56: 82-9 |
| PMID | 24888672 |
| Title | Temperament and character in remitted and symptomatic patients with schizophrenia: modulation by the COMT Val158Met genotype. |
| Abstract | While research on remission in schizophrenia has gained attention, personality characteristics associated with remission in schizophrenia have been under-studied. A functional valine-to-methionine (Val158Met) polymorphism in the catechol-O-methyltransferase (COMT) gene is shown to modify clinical presentation of schizophrenia despite weak or no association with the disorder itself. Studies also report that this polymorphism can affect personality traits. We aimed to examine personality traits of remitted patients with schizophrenia as compared to symptomatic patients and healthy controls and to investigate whether the COMT Val158Met polymorphism influences their personality. Scores on the Temperament and Character Inventory were compared between 34 remitted outpatients with schizophrenia, age- and sex-matched 72 symptomatic outpatients with schizophrenia, and matched 247 healthy individuals. The effect of COMT Val158Met polymorphism on personality was examined in each group. The analysis of covariance, controlling for confounding variables, revealed that compared to healthy controls, symptomatic patients exhibited a pervasively altered personality profile whereas remitted patients showed alterations in more limited personality dimensions and demonstrated normal levels of novelty-seeking, reward dependence and cooperativeness. The two-way analysis of covariance, with genotype and sex as between-subject factors and confounders as covariates, revealed that Met carriers demonstrated significantly lower reward dependence and cooperativeness than Val homozygotes in symptomatic patients; while no significant genotype effect was found in remitted patients or in healthy individuals. These findings indicate that remitted patients with schizophrenia have a relatively adaptive personality profile compared to symptomatic patients. The COMT Val158Met polymorphism might have a modulating effect on the relationship between personality and remission. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 555 | J Psychiatr Res 2014 Sep 56: 28-35 |
| PMID | 24853458 |
| Title | Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects. |
| Abstract | The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals. Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 556 | Epigenetics 2014 Aug 9: 1101-7 |
| PMID | 24837210 |
| Title | MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls. |
| Abstract | Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 557 | Genet. Mol. Res. 2014 -1 13: 3079-88 |
| PMID | 24782165 |
| Title | Genetic association of catechol-O-methyltransferase val(158)met polymorphism in Saudi schizophrenia patients. |
| Abstract | schizophrenia is a complex neuropsychiatric disorder strongly associated with dopamine dysregulation. Catechol-O-methyl-transferase (COMT) is a candidate gene for schizophrenia that encodes an enzyme involved in the metabolic inactivation of dopamine. The COMT Val(158)Met polymorphism has been associated with schizophrenia and has significant inter- and intra-ethnic variations. We examined a possible association between the COMT Val(158)Met polymorphism and schizophrenia in Saudis, taking into account gender and functional symptoms. Saudi subjects including 172 unrelated schizophrenia patients and 177 matched controls were analyzed for allele and genotype distribution of the COMT Val(158)Met polymorphism. We found significant differences in allele and genotype frequencies between patients and controls. The frequencies of Met(158) allele (A) and genotype Val(158)Met (GA) were significantly higher in patients compared to those in controls. On the other hand, the frequencies of Val(158) allele (G) and genotype Val(158)Val (GG) were significantly higher in controls than those in patients. We found a significant association of the COMT Val(158)Met polymorphism with schizophrenia. Moreover, male patients with the COMT Val(158)Met polymorphism had increased risk for schizophrenia compared to female subjects. However, no association was noticed with the COMT Val(158)Met polymorphism and negative or positive symptoms of schizophrenia. These results provide evidence for a role of the COMT Val(158)Met polymorphism in the etiopathophysiology of schizophrenia in Saudi population. It appears that the association of the COMT Val(158)Met polymorphism with schizophrenia is mediated by gender. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 558 | Int. J. Neuropsychopharmacol. 2014 Oct 17: 1707-13 |
| PMID | 24735585 |
| Title | Methionine sulfoxide reductase regulates brain catechol-O-methyl transferase activity. |
| Abstract | Catechol-O-methyl transferase (COMT) plays a key role in the degradation of brain dopamine (DA). Specifically, low COMT activity results in higher DA levels in the prefrontal cortex (PFC), thereby reducing the vulnerability for attentional and cognitive deficits in both psychotic and healthy individuals. COMT activity is markedly reduced by a non-synonymous single-nucleotide polymorphism (SNP) that generates a valine-to-methionine substitution on the residue 108/158, by means of as-yet incompletely understood post-translational mechanisms. One post-translational modification is methionine sulfoxide, which can be reduced by the methionine sulfoxide reductase (Msr) A and B enzymes. We used recombinant COMT proteins (Val/Met108) and mice (wild-type (WT) and MsrA knockout) to determine the effect of methionine oxidation on COMT activity and COMT interaction with Msr, through a combination of enzymatic activity and Western blot assays. Recombinant COMT activity is positively regulated by MsrA, especially under oxidative conditions, whereas brains of MsrA knockout mice exhibited lower COMT activity (as compared with their WT counterparts). These results suggest that COMT activity may be reduced by methionine oxidation, and point to Msr as a key molecular determinant for the modulation of COMT activity in the brain. The role of Msr in modulating cognitive functions in healthy individuals and schizophrenia patients is yet to be determined. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 559 | Psychiatry Res 2014 Jun 217: 9-14 |
| PMID | 24656901 |
| Title | Factors affecting cognitive remediation response in schizophrenia: the role of COMT gene and antipsychotic treatment. |
| Abstract | Cognitive remediation is the best available tool to treat cognitive deficits in schizophrenia and has evidence of biological validity; however results are still heterogeneous and significant predictors are lacking. Previous studies showed that cognitive remediation is able to induce changes in PFC function and dopaminergic transmission and thus the study of possible sources of variability at these levels (i.e. antipsychotic treatments and genetic variability) might help to gain a deeper understanding of neurobiological correlates and translate into optimization and personalization of interventions. In the present study, we analyzed the interaction between pharmacological treatment (clozapine vs typical/atypical D2 blockers) and COMT rs4680 polymorphism on cognitive changes after cognitive remediation therapy, in a sample of 98 clinically stabilized patients with schizophrenia. The General Linear Model showed a significant interaction of pharmacological treatment and COMT polymorphism on the improvement in "Symbol Coding" subtest, a global measure of speed of processing. Post-hoc analysis revealed a significant difference between COMT genotypes, when treated with D2 blockers, with worse results among Val/Val patients. These preliminary results suggest that genetic variability, influencing prefrontal dopamine, might affect individual capacity to improve with different patterns, depending on antipsychotic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 560 | Front Behav Neurosci 2014 -1 8: 71 |
| PMID | 24639636 |
| Title | Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission. |
| Abstract | schizophrenia is a severe mental disorder, with a highly complex and heterogenous clinical presentation. Our current perspectives posit that the pathogenic mechanisms of this illness lie in complex arrays of gene × environment interactions. Furthermore, several findings indicate that males have a higher susceptibility for schizophrenia, with earlier age of onset and overall poorer clinical prognosis. Based on these premises, several authors have recently begun exploring the possibility that the greater schizophrenia vulnerability in males may reflect specific gene × sex (G×S) interactions. Our knowledge on such G×S interactions in schizophrenia is still rudimentary; nevertheless, the bulk of preclinical evidence suggests that the molecular mechanisms for such interactions are likely contributed by the neurobiological effects of sex steroids on dopamine (DA) neurotransmission. Accordingly, several recent studies suggest a gender-specific association of certain DAergic genes with schizophrenia. These G×S interactions have been particularly documented for catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), the main enzymes catalyzing DA metabolism. In the present review, we will outline the current evidence on the interactions of DA-related genes and sex-related factors, and discuss the potential molecular substrates that may mediate their cooperative actions in schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 561 | Cereb. Cortex 2014 May 24: 1230-46 |
| PMID | 23283688 |
| Title | Common variants in psychiatric risk genes predict brain structure at birth. |
| Abstract | Studies in adolescents and adults have demonstrated that polymorphisms in putative psychiatric risk genes are associated with differences in brain structure, but cannot address when in development these relationships arise. To determine if common genetic variants in disrupted-in-schizophrenia-1 (DISC1; rs821616 and rs6675281), catechol-O-methyltransferase (COMT; rs4680), neuregulin 1 (NRG1; rs35753505 and rs6994992), apolipoprotein E (APOE; ?3?4 vs. ?3?3), estrogen receptor alpha (ESR1; rs9340799 and rs2234693), brain-derived neurotrophic factor (BDNF; rs6265), and glutamate decarboxylase 1 (GAD1; rs2270335) are associated with individual differences in brain tissue volumes in neonates, we applied both automated region-of-interest volumetry and tensor-based morphometry to a sample of 272 neonates who had received high-resolution magnetic resonance imaging scans. ESR1 (rs9340799) predicted intracranial volume. Local variation in gray matter (GM) volume was significantly associated with polymorphisms in DISC1 (rs821616), COMT, NRG1, APOE, ESR1 (rs9340799), and BDNF. No associations were identified for DISC1 (rs6675281), ESR1 (rs2234693), or GAD1. Of note, neonates homozygous for the DISC1 (rs821616) serine allele exhibited numerous large clusters of reduced GM in the frontal lobes, and neonates homozygous for the COMT valine allele exhibited reduced GM in the temporal cortex and hippocampus, mirroring findings in adults. The results highlight the importance of prenatal brain development in mediating psychiatric risk. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 562 | Schizophr. Res. 2014 Mar 153: 231-6 |
| PMID | 24534796 |
| Title | Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of psychotic disorder, particularly schizophrenia. The deletion is considered to be a biological model for understanding this debilitating psychiatric disorder. It is unclear whether the psychotic manifestations in 22q11.2DS are similar to those in schizophrenia patients without the deletion. Catechol-O-methyltransferase (COMT), a positional candidate gene for schizophrenia, resides within the 22q11.2 region. It remains unknown whether hemizygosity for this gene is associated with risk of psychotic disorder. This study includes 83 adults with 22q11.2DS, 90 non-deleted individuals with schizophrenia, and 316 normal controls. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry, the Schedules for the Assessment of Positive and Negative Symptoms and the Global Assessment Scale. schizotypy was assessed with the Kings schizotypy Questionnaire and Oxford Liverpool Inventory of Feelings and Emotions. IQ estimates were also obtained. Adults with 22q11.2DS were genotyped for a number of COMT polymorphisms as well as the Ashkenazi risk haplotype. This study confirms high rates of psychotic disorder (29%) in individuals with 22q11.2DS of which the majority had schizophrenia (22%). There does not appear to be a differential expression of schizophrenic symptom clusters in 22q11.2DS in relation to sporadic schizophrenia, though schizophrenia in 22q11.2DS seems to be less severe in terms of global assessment scores. Psychosis proneness seems to be of genetic origin in 22q11.2DS as individuals with 22q11.2DS without schizophrenia had higher schizotypy scores than normal controls. Finally, COMT was not associated with schizophrenia status or schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 563 | Psychopharmacology (Berl.) 2014 May 231: 2211-8 |
| PMID | 24448899 |
| Title | Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype. |
| Abstract | Metabolic syndrome (MetS) has consistently been identified as an adverse effect of long-term treatment with atypical antipsychotics (AAPs) such as clozapine. Elevated serum homocysteine concentration has been found to act as an independent risk factor for MetS, and catechol-O-methyltransferase (COMT) catalyzes the homocysteine metabolism. We accordingly hypothesized that COMT dysregulation may confer the susceptibility to MetS induced by AAPs, potentially in a gender-specific manner, because the interaction effects of COMT and gender have been consistently reported. This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment. A total of 468 schizophrenia patients taking clozapine were divided into two groups, those experiencing MetS and non-MetS. We genotyped three functional variants (rs4633, rs4680, and rs4818) in COMT and measured the serum levels of fasting homocysteine, glucose, triglyceride (TG), and high-density lipoprotein cholesterol. MetS was found in 202/468 (43.2 %) of all the patients, with 40.2 % prevalence (138/343) in males and 51.2 % (64/125) in females. Patients with MetS had notably higher metabolic parameters than those without MetS. The mean levels of homocysteine in patients with MetS were significantly higher than those without MetS. We found a positive association between the rs4680 polymorphism and the serum triglyceride levels (corrected P?=?0.024). Further analysis revealed that the rs4680 Met allele was significantly associated with increased triglyceride levels among female patients (P?=?0.009), but not among males (P?=?0.07). Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 564 | Neuromolecular Med. 2014 Jun 16: 398-404 |
| PMID | 24443099 |
| Title | Effect of COMT Val108/158Met genotype on risk for polydipsia in chronic patients with schizophrenia. |
| Abstract | Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val(108/158)Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val(108/158)Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the ?(2) test. A significant association between the COMT Val(108/158)Met polymorphism and polydipsia was found (genotype distribution: ?(2) = 13.0, df = 2, p = 0.001; allele frequency: ?(2) = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val(108/158)Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 565 | Health Psychol Behav Med 2014 Jan 2: 509-516 |
| PMID | 25750798 |
| Title | COMT and 5-HT1A-receptor genotypes potentially affect executive functions improvement after cognitive remediation in schizophrenia. |
| Abstract | Cognitive remediation therapy (CRT) has been proved to improve cognitive deficits in schizophrenia and to enhance functional outcomes of classical rehabilitation. However, CRT outcomes are heterogeneous and predictors of response are still unknown. Genetic variability, especially in the dopaminergic system, has been hypothesized to affect CRT. We previously reported that rs4680 of the catechol-O-methyltrasferase (COMT) influences improvements in executive functions in patients treated with CRT, but this result was not confirmed by other studies. Such inconsistent findings may depend, other than on clinical variables, also on other genes involved in cognition. Recent studies proved that serotonin 1A receptor (5-HT1A-R) regulates dopamine in the prefrontal cortex (PFC), and clinical works suggested a 5-HT1A-R role in cognition. We then analysed possible effects of COMT rs4680 and 5-HT1A-R rs6295 on CRT outcomes, taking into account also clinical and demographic factors. Eighty-six clinically stabilized schizophrenia patients treated with three?months CRT were assessed with the Wisconsin Card Sorting Test, as a measure of executive functions, at enrolment and after CRT treatment, and underwent COMT and 5-HT1A-R genotyping. We found a significant main effect of COMT genotype and an interaction with 5-HT1A-R on executive function improvement after CRT. The results suggest that these two polymorphisms may have an additive effect on individual capacity to recover from cognitive deficit, probably through their role on PFC dopaminergic transmission modulation, known to be critical for modulating cognitive functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 566 | J Psychiatr Res 2014 Feb 49: 43-50 |
| PMID | 24252819 |
| Title | Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia. |
| Abstract | The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition and symptoms in schizophrenia were moderated by the Catechol-O-methyltransferase (COMT) Val(158)Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val(158)Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 567 | Biol. Psychiatry 2014 Mar 75: 406-13 |
| PMID | 23992923 |
| Title | Biological effects of COMT haplotypes and psychosis risk in 22q11.2 deletion syndrome. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS. Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing control subjects. We measured COMT messenger (m)RNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing. There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3' untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3' untranslated region single nucleotide polymorphism, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 "T" mutation is associated with absent soluble COMT expression and very low COMT activity in two 22q11.2DS individuals. Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 568 | Genes Brain Behav. 2014 Jan 13: 104-17 |
| PMID | 23927712 |
| Title | Theory of mind and the social brain: implications for understanding the genetic basis of schizophrenia. |
| Abstract | Genome-wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging-based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First-episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub-types for further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 569 | Addict Biol 2014 Jul 19: 722-32 |
| PMID | 23311613 |
| Title | Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users. |
| Abstract | Neuroimaging studies have shown that chronic consumption of cannabis may result in alterations in brain morphology. Recent work focusing on the relationship between brain structure and the catechol-O-methyltransferase (COMT) gene polymorphism suggests that functional COMT variants may affect brain volume in healthy individuals and in schizophrenia patients. We measured the influence of COMT genotype on the volume of four key regions: the prefrontal cortex, neostriatum (caudate-putamen), anterior cingulate cortex and hippocampus-amygdala complex, in chronic early-onset cannabis users and healthy control subjects. We selected 29 chronic cannabis users who began using cannabis before 16 years of age and matched them to 28 healthy volunteers in terms of age, educational level and IQ. Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition. COMT genotyping was performed and structural magnetic resonance imaging data was analyzed by voxel-based morphometry. The results showed that the COMT polymorphism influenced the volume of the bilateral ventral caudate nucleus in both groups, but in an opposite direction: more copies of val allele led to lesser volume in chronic cannabis users and more volume in controls. The opposite pattern was found in left amygdala. There were no effects of COMT genotype on volumes of the whole brain or the other selected regions. Our findings support recent reports of neuroanatomical changes associated with cannabis use and, for the first time, reveal that these changes may be influenced by the COMT genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 570 | Int. J. Neuropsychopharmacol. 2014 Feb 17: 337-40 |
| PMID | 24229565 |
| Title | Entacapone augmentation of antipsychotic treatment in schizophrenic patients with negative symptoms; a double-blind placebo-controlled study. |
| Abstract | Negative symptoms in schizophrenia are associated with decreased dopaminergic activity in the prefrontal cortex (PFC). It is hypothesized that increasing dopamine levels would alleviate negative symptoms. Termination of dopamine activity in the PFC is mainly via catechol-O-methyl tranferase (COMT) activity. Hence, inhibition of COMT activity with entacapone should reverse PFC dopaminergic transmission. To assess the efficacy of entacapone addition to antipsychotic treatment in patients with residual schizophrenia, we conducted a double-blind, randomised, placebo-controlled study for 12 wk of treatment with entacapone or placebo. Clinical measures (PANSS, CGI and QLS) were obtained at baseline and at weeks 4, 8 and 12 and cognitive functions were assessed by the RBANSS. Significant improvement over time in PANSS and QLS scores was observed in both groups. However, entacapone did not demonstrate a beneficial effect compared to placebo. Therefore, this study does not support a therapeutic role for entacapone in residual schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 571 | Eur. Psychiatry 2014 Jun 29: 304-6 |
| PMID | 24630741 |
| Title | Psychosis-proneness correlates with expression levels of dopaminergic genes. |
| Abstract | Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 572 | Schizophr. Res. 2014 Mar 153: 231-6 |
| PMID | 24534796 |
| Title | Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of psychotic disorder, particularly schizophrenia. The deletion is considered to be a biological model for understanding this debilitating psychiatric disorder. It is unclear whether the psychotic manifestations in 22q11.2DS are similar to those in schizophrenia patients without the deletion. Catechol-O-methyltransferase (COMT), a positional candidate gene for schizophrenia, resides within the 22q11.2 region. It remains unknown whether hemizygosity for this gene is associated with risk of psychotic disorder. This study includes 83 adults with 22q11.2DS, 90 non-deleted individuals with schizophrenia, and 316 normal controls. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry, the Schedules for the Assessment of Positive and Negative Symptoms and the Global Assessment Scale. schizotypy was assessed with the Kings schizotypy Questionnaire and Oxford Liverpool Inventory of Feelings and Emotions. IQ estimates were also obtained. Adults with 22q11.2DS were genotyped for a number of COMT polymorphisms as well as the Ashkenazi risk haplotype. This study confirms high rates of psychotic disorder (29%) in individuals with 22q11.2DS of which the majority had schizophrenia (22%). There does not appear to be a differential expression of schizophrenic symptom clusters in 22q11.2DS in relation to sporadic schizophrenia, though schizophrenia in 22q11.2DS seems to be less severe in terms of global assessment scores. Psychosis proneness seems to be of genetic origin in 22q11.2DS as individuals with 22q11.2DS without schizophrenia had higher schizotypy scores than normal controls. Finally, COMT was not associated with schizophrenia status or schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 573 | Front Psychiatry 2014 -1 5: 54 |
| PMID | 24904437 |
| Title | Gone to Pot - A Review of the Association between Cannabis and Psychosis. |
| Abstract | Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 574 | Schizophr. Res. 2014 Mar 153: 231-6 |
| PMID | 24534796 |
| Title | Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. |
| Abstract | 22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of psychotic disorder, particularly schizophrenia. The deletion is considered to be a biological model for understanding this debilitating psychiatric disorder. It is unclear whether the psychotic manifestations in 22q11.2DS are similar to those in schizophrenia patients without the deletion. Catechol-O-methyltransferase (COMT), a positional candidate gene for schizophrenia, resides within the 22q11.2 region. It remains unknown whether hemizygosity for this gene is associated with risk of psychotic disorder. This study includes 83 adults with 22q11.2DS, 90 non-deleted individuals with schizophrenia, and 316 normal controls. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry, the Schedules for the Assessment of Positive and Negative Symptoms and the Global Assessment Scale. schizotypy was assessed with the Kings schizotypy Questionnaire and Oxford Liverpool Inventory of Feelings and Emotions. IQ estimates were also obtained. Adults with 22q11.2DS were genotyped for a number of COMT polymorphisms as well as the Ashkenazi risk haplotype. This study confirms high rates of psychotic disorder (29%) in individuals with 22q11.2DS of which the majority had schizophrenia (22%). There does not appear to be a differential expression of schizophrenic symptom clusters in 22q11.2DS in relation to sporadic schizophrenia, though schizophrenia in 22q11.2DS seems to be less severe in terms of global assessment scores. Psychosis proneness seems to be of genetic origin in 22q11.2DS as individuals with 22q11.2DS without schizophrenia had higher schizotypy scores than normal controls. Finally, COMT was not associated with schizophrenia status or schizotypy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 575 | Psychiatr. Genet. 2015 Jun 25: 131-4 |
| PMID | 25748092 |
| Title | Catechol-O-methyltransferase genotype and response to Compensatory Cognitive Training in outpatients with schizophrenia. |
| Abstract | The catechol-O-methyltransferase (COMT) ValMet polymorphism is associated with cognitive functioning in schizophrenia and may predict cognitive training outcomes. This study aimed to explore the contribution of COMT genotype in predicting improvement following Compensatory Cognitive Training (CCT). We conducted mixed factorial analysis of variance to examine COMT genotype as a predictor of response to CCT (i.e. improved cognitive performance) in 41 participants with schizophrenia-spectrum disorders. We also explored the effect of CCT treatment and COMT genotype on psychiatric symptom severity, functional capacity, and subjective quality of life. Met carrier status did not predict CCT treatment outcomes. COMT genotype may exert only modest effects on cognitive training response. Further research with larger samples is needed to establish genetic predictors of response to cognitive training. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 576 | Asian J Psychiatr 2015 Oct 17: 107-8 |
| PMID | 26300284 |
| Title | Aggression in Malaysian schizophrenia patients: Its clinical determinants and association with COMT Val158Met genotypes. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 577 | Asian J Psychiatr 2015 Aug 16: 75-7 |
| PMID | 26070413 |
| Title | Effect of tDCS on auditory hallucinations in schizophrenia: Influence of catechol-O-methyltransferase (COMT) Val158Met polymorphism. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 578 | Mol. Neurobiol. 2015 Oct -1: -1 |
| PMID | 26491028 |
| Title | Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis. |
| Abstract | In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-?) were analyzed in 174 antipsychotic naïve first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine?×?treatment?×?gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 579 | Eur Neuropsychopharmacol 2015 Dec 25: 2349-63 |
| PMID | 26560201 |
| Title | Sex-dichotomous effects of functional COMT genetic variations on cognitive functions disappear after menopause in both health and schizophrenia. |
| Abstract | Different genetic variations in the catechol-O-methyltransferase (COMT) gene have been indicated to functionally regulate the encoded enzyme. Despite the vast literature on the single nucleotide COMT ValMet polymorphism, the impact of complex haplotypes on cognitive functions has been overlooked. Here we contrasted the effects of complex COMT haplotypes with the ValMet polymorphism on cognitive functions and their interaction with menopause, in healthy subjects and patients with schizophrenia. Healthy adults (N=229) as well as patients with schizophrenia (N=172) underwent a comprehensive cognitive assessment taking into account the menopausal state. Functional COMT variations selectively modulated working memory and executive functions. Strikingly, these effects were present only in adult men but not in women before menopause, in both healthy subjects and patients with schizophrenia. Importantly, the same pattern of COMT-dependent effects present in men reappeared in women after menopause. Thus, functional COMT mutations seem to modulate cognitive functions depending on the hormonal status. These data clarify the importance of taking into account the combined effect of sex, hormonal status and genetics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 580 | CNS Neurol Disord Drug Targets 2015 -1 14: 1086-95 |
| PMID | 25801838 |
| Title | Association of Single Nucleotide Polymorphisms in Catechol-O-Methyltransferase and Serine-Threonine Protein Kinase Genes in the Pakistani Schizophrenic Population: A Study with Special Emphasis on Cannabis and Smokeless Tobacco. |
| Abstract | schizophrenia is a neuropsychiatric disorder in which abnormalities in the prefrontal cortex lead to impaired synthesis of dopamine. It is associated with hallucination, psychosis and hearing impairments. Many susceptible genes have been identified in schizophrenia such as catechol-O-methyltransferase (COMT) and serine/threonine kinase (AKT1). Single nucleotide polymorphisms (SNPs) in these genes have not been identified in Pakistan. Therefore, we investigated the allelic and genotypic frequencies in COMT and AKT1 genes in the Pakistani population. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used to identify SNPs in the genes. The present study shows that COMT Val and COMT Met allelic frequencies for the controls were p=0.52, q=0.48 and for the schizophrenic cases they were p=0.34, q=0.66 respectively. The distribution of polymorphism in COMT Val158Met genotype by Hardy-Weinberg equilibrium (HWE) was P=0.61 for controls and P=0.005 for cases. The data reveal that SNP rs1130214 T allele mutation was found neither in patients nor in controls in the 5' untranslated region (UTR). This proves that no association of AKT1 and positive association of COMT with schizophrenia exist in the population of Pakistan. Moreover, a study based on a single family showed COMT Met allele inheritance in schizophrenic offspring. This suggested that COMT allele alteration influences susceptibility to at least some forms of psychosis in the Pakistani population. Interestingly, according to our socio-economical survey, COMT genotype has no association with cannabis but it is strongly associated with tobacco. The Pakistani population with Val158Met SNP showed more susceptibility towards developing schizophrenia. This study highlights the genetic differences between Pakistani and other Caucasian populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 581 | Ann. Hum. Genet. 2015 Mar -1: -1 |
| PMID | 25817274 |
| Title | Investigation of Recessive Effects in Schizophrenia Using Next-Generation Exome Sequence Data. |
| Abstract | A number of gene-wise approaches to analysis were applied to whole exome sequence data from 2545 Swedish schizophrenia cases with 2545 matched controls. A weighted burden test was used to detect dominant and additive effects. Recessive effects were investigated by testing whether there was an excess of cases bearing two or more rare, functional variants or whether there was an excess of cases in which both phased haplotypes carried at least one rare, functional variant. Counts for cases were compared with controls and also with the expectation under Hardy-Weinberg equilibrium. Analyses were performed using the SCOREASSOC program. No gene produced statistically significant results although COMT was highly ranked by the weighted burden test and within it the Ala72Ser polymorphism rs6267 had an uncorrected p value of 0.00003. A number of spurious results were generated, some apparently due to miscalling of homozygotes and others due to a failure to eradicate the effects of linkage disequilibrium between variants. These problems were not marked when using phased haplotypes but this method failed to produce any significant or suggestive findings. If there are exonic variants with recessive effects on the risk of schizophrenia, then the methods used were unable to detect them. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 582 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Jan 56: 149-54 |
| PMID | 25194460 |
| Title | Perinatal asphyxia alters neuregulin-1 and COMT gene expression in the medial prefrontal cortex in rats. |
| Abstract | Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12 weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12 weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12 weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 583 | ACS Med Chem Lett 2015 Mar 6: 318-23 |
| PMID | 25815153 |
| Title | Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT). |
| Abstract | 3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 584 | Mol. Psychiatry 2015 May 20: 555-62 |
| PMID | 25754081 |
| Title | Evaluating historical candidate genes for schizophrenia. |
| Abstract | Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 585 | J Psychiatr Res 2015 Jan 60: 1-13 |
| PMID | 25287955 |
| Title | Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. |
| Abstract | Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 586 | Prilozi 2015 -1 36: 53-67 |
| PMID | 26076775 |
| Title | Pharmacogenetics and antipsychotic treatment response. |
| Abstract | (Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 587 | Schizophr. Res. 2015 Oct 168: 402-10 |
| PMID | 26164821 |
| Title | Postnatal neurodevelopmental expression and glutamate-dependent regulation of the ZNF804A rodent homologue. |
| Abstract | The zinc finger protein ZNF804A rs1344706 variant is a replicated genome-wide significant risk variant for schizophrenia and bipolar disorder. While its association with altered brain structure and cognition in patients and healthy risk allele carriers is well documented, the characteristics and function of the gene in the brain remains poorly understood. Here, we used in situ hybridization to determine mRNA expression levels of the ZNF804A rodent homologue, Zfp804a, across multiple postnatal neurodevelopmental time points in the rat brain. We found changes in Zfp804a expression in the rat hippocampus, frontal cortex, and thalamus across postnatal neurodevelopment. Zfp804a mRNA peaked at postnatal day (P) 21 in hippocampal CA1 and DG regions and was highest in the lower cortical layers of frontal cortex at P1, possibly highlighting a role in developmental migration. Using immunofluorescence, we found that Zfp804a mRNA and ZFP804A co-localized with neurons and not astrocytes. In primary cultured cortical neurons, we found that Zfp804a expression was significantly increased when neurons were exposed to glutamate [20?M], but this increase was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. Expression of COMT, Pde4b, and Drd2, genes previously shown to be regulated by ZNF804A overexpression, was also significantly changed in an NMDA-dependent manner. Our results describe, for the first time, the unique postnatal neurodevelopmental expression of Zfp804a in the rodent brain and demonstrate that glutamate potentially plays an important role in the regulation of this psychiatric susceptibility gene. These are critical steps toward understanding the biological function of ZNF804A in the mammalian brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 588 | Neuropsychopharmacology 2015 May 40: 1353-63 |
| PMID | 25418810 |
| Title | Dissociable deficits of executive function caused by gestational adversity are linked to specific transcriptional changes in the prefrontal cortex. |
| Abstract | Poor-quality maternal diet during pregnancy, and subsequent gestational growth disturbances in the offspring, have been implicated in the etiology of multiple neurodevelopmental disorders, including ADHD, schizophrenia, and autism. These disorders are characterized, in part, by abnormalities in responses to reward and errors of executive function. Here, we demonstrate dissociable deficits in reward processing and executive function in male and female mice, solely due to maternal malnutrition via high-fat or low-protein diets. Gestational exposure to a high-fat diet delayed acquisition of a fixed ratio response, and decreased motivation as assessed by progressive ratio. In contrast, offspring of a low-protein diet displayed no deficits in operant learning, but were more prone to assign salience to a cue that predicts reward (sign-tracking) in a Pavlovian-conditioned approach task. In the 5-choice serial reaction time task (5-CSRTT), gestational exposure to a high-fat diet promoted impulsivity, whereas exposure to a low-protein diet led to marked inattention. These dissociable executive function deficits are known to be mediated by the medial prefrontal cortex (PFC), which displays markers of epigenetic dysregulation in neurodevelopmental disorders. Following behavioral characterization, we assayed PFC gene expression using a targeted PCR array and found that both maternal diets increased overall transcription in PFC. Cluster analysis of the relationships between individual transcripts and behavioral outcomes revealed a cluster of primarily epigenetic modulators, whose overexpression was linked to executive function deficits. The overexpression of four genes, DNA methyltransferase 1 (DNMT1), ?-opioid receptor (OPRD1), cannabinoid receptor 1 (CNR1), and catechol-o-methyltransferase (COMT), was strongly associated with overall poor performance. All 5-CSRTT deficits were associated with DNMT1 upregulation, whereas impulsive behavior could be dissociated from inattention by overexpression of OPRD1 or COMT, respectively, as well as a distinct cluster of epigenetic regulators. These data provide molecular support for dissociable domains of executive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 589 | Addict Biol 2015 Jan 20: 197-204 |
| PMID | 24118473 |
| Title | Val158Met COMT polymorphism and risk of aggression in alcohol dependence. |
| Abstract | Aggression, violence and antisocial behavior are common in alcoholism, but their biological basis is poorly understood. Several studies and recent meta-analyses indicate that in schizophrenia the catecholamine-O-methyltransferase (COMT) Val158Met genotype may be associated with aggression, most often in methionine allele carriers. We tested this hypothesis in a sample of treatment-seeking alcohol-dependent in-patients (293 German patients and 499 controls, and additional 190 Polish patients as replication sample). As expected, patients with a history of violent or non-violent crime were more often male, had an earlier onset of alcoholism and more withdrawal seizures and delirium tremens, and were more likely to have a history of suicide attempts. COMT genotype was not associated with a history of violent or non-violent crime. More studies are needed on the neurobiological basis of aggression and violence in alcoholism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 590 | Pharmacogenomics J. 2015 Aug -1: -1 |
| PMID | 26282453 |
| Title | Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population. |
| Abstract | schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population. Continuous long-term treatment is required to maintain social functioning and prevent symptom relapse of schizophrenia patients. However, there are considerable individual differences in response to the antipsychotic drugs. There is a pressing need to identify more drug-response-related markers. But most pharmacogenomics of schizophrenia have typically focused on a few candidate genes in small sample size. In this study, 995 subjects were selected for discovering the drug-response-related markers. A total of 77 single-nucleotide polymorphisms of 25 genes have been investigated for four commonly used antipsychotic drugs in China: risperidone, clozapine, quetiapine, and chlorpromazine. Significant associations with treatment response for several genes, such as CYP2D6, CYP2C19, COMT, ABCB1, DRD3 and HTR2C have been verified in our study. Also, we found several new candidate genes (TNIK, RELN, NOTCH4 and SLC6A2) and combinations (haplotype rs1544325-rs5993883-rs6269-rs4818 in COMT) that are associated with treatment response to the four drugs. Also, multivariate interactions analysis demonstrated the combination of rs6269 in COMT and rs3813929 in HTR2C may work as a predictor to improve the clinical antipsychotic response. So our study is of great significance to improve current knowledge on the pharmacogenomics of schizophrenia, thus promoting the implementation of personalized medicine in schizophrenia.The Pharmacogenomics Journal advance online publication, 18 August 2015; doi:10.1038/tpj.2015.61. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 591 | Schizophr. Res. 2015 Oct 168: 279-84 |
| PMID | 26255563 |
| Title | COMT genotype and response to cognitive remediation in schizophrenia. |
| Abstract | A functional polymorphism of the catechol-O-methyltransferase (COMT) gene (Val158Met) partially appears to influence cognitive performance in schizophrenia subjects and healthy controls by modulating prefrontal dopaminergic activity. This study evaluated the association of the COMT Val108/158 Met genotype with response to computerized neurocognitive remediation (CRT). 145 subjects with DSM-IV-TR schizophrenia or schizoaffective disorder were genotyped via saliva sampling. Subjects were evaluated on neurocognitive assessments (MATRICS) and clinical symptoms (PANSS) at baseline and endpoint after 12weeks of CRT. "Improvement" was defined as ?67% of cognitive domains (?4) showing performance increases. If ?67% (?2) of domains improved, the change was defined as "minimal improvement." A general linear model was conducted for change of each cognitive domain. Of 145 subjects, data from 138 subjects were usable. Distribution of COMT genotype: Met/Met: 28 (20.29%), Val/Met: 61 (44.20%), and Val/Val: 49 (35.51%). No significant differences were seen among genotype groups at baseline or across genotype group for "Improvement" vs. "Minimal Improvement." GLM analysis showed significant differences in Verbal Learning (p=0.003), Visual Learning (p=0.014) and Attention/Vigilance (p=0.011) favoring Met/Met and Val/Met groups. The low activity Met allele (Met/Met; Val/Met) was associated with significantly greater improvements in the MATRICS domains of Verbal Learning, Visual Learning and Attention/Vigilance after CRT. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 592 | J. Biol. Chem. 2015 Sep 290: 23240-53 |
| PMID | 26221035 |
| Title | Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome. |
| Abstract | The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of ?30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of ?-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1?, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 593 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 649-59 |
| PMID | 26198764 |
| Title | Genome-wide association study of schizophrenia in Ashkenazi Jews. |
| Abstract | schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R(2) ?9.7%) and a SNP-heritability estimate of 0.39 (P?=?0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10(-6) -10(-7) range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P? |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 594 | Hum. Mutat. 2015 Aug 36: 797-807 |
| PMID | 25981510 |
| Title | Whole-Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations. |
| Abstract | The 22q11.2 deletion syndrome (22q11DS) affects 1:4,000 live births and presents with highly variable phenotype expressivity. In this study, we developed an analytical approach utilizing whole-genome sequencing (WGS) and integrative analysis to discover genetic modifiers. Our pipeline combined available tools in order to prioritize rare, predicted deleterious, coding and noncoding single-nucleotide variants (SNVs), and insertion/deletions from WGS. We sequenced two unrelated probands with 22q11DS, with contrasting clinical findings, and their unaffected parents. Proband P1 had cognitive impairment, psychotic episodes, anxiety, and tetralogy of Fallot (TOF), whereas proband P2 had juvenile rheumatoid arthritis but no other major clinical findings. In P1, we identified common variants in COMT and PRODH on 22q11.2 as well as rare potentially deleterious DNA variants in other behavioral/neurocognitive genes. We also identified a de novo SNV in ADNP2 (NM_014913.3:c.2243G>C), encoding a neuroprotective protein that may be involved in behavioral disorders. In P2, we identified a novel nonsynonymous SNV in ZFPM2 (NM_012082.3:c.1576C>T), a known causative gene for TOF, which may act as a protective variant downstream of TBX1, haploinsufficiency of which is responsible for congenital heart disease in individuals with 22q11DS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 595 | Clin Psychopharmacol Neurosci 2015 Apr 13: 68-82 |
| PMID | 25912540 |
| Title | Effect of polymorphisms of three genes mediating monoamine signalling on brain morphometry in schizophrenia and healthy subjects. |
| Abstract | We examined the effect of risk alleles of polymorphisms of three schizophrenia risk genes that mediate monoamine signalling in the brain on regional brain volumes of schizophrenia and healthy control subjects. The risk alleles and the gene polymorphisms studied were: Val allele of catechol o-methyltransferase (COMT) rs4680 polymorphism; short allele of 5-hydroxy tryptamine transporter linked polymorphic region (5HTTLPR) polymorphism; and T allele of 5-hydroxy tryptamine 2A (5HT2A) rs6314 polymorphism. The study was carried out on patients with recent onset schizophrenia (n=41) recruited from the outpatient department of National Institute of Mental Health and Neurosciences, Bangalore, India and healthy control subjects (n=39), belonging to South Indian Dravidian ethnicity. Individual and additive effects of risk alleles of the above gene polymorphisms on brain morphometry were explored using voxel-based morphometry. Irrespective of phenotypes, individuals with the risk allele T of the rs6314 polymorphism of 5HT2A gene showed greater (at cluster-extent equivalent to family wise error-correction [FWEc] p<0.05) regional brain volumes in the left inferior temporal and left inferior occipital gyri. Those with the risk alleles of the other two polymorphisms showed a trend (at p<0.001, uncorrected) towards lower regional brain volumes. A trend (at p<0.001, uncorrected) towards additive effects of the above 3 risk alleles (subjects with 2 or 3 risk alleles vs. those with 1 or no risk alleles) on brain morphology was also noted. The findings of the present study have implications in understanding the role of individual and additive effects of genetic variants in mediating regional brain morphometry in health and disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 596 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2015 Apr 32: 259-63 |
| PMID | 25863100 |
| Title | [Difference in brain surface area between first-episode familial and sporadic schizophrenia and its association with COMT gene polymorphisms]. |
| Abstract | To assess the association of impairment of surface area of first-episode schizophrenia(SZ) with polymorphisms of COMT gene, and the difference in the impaired patterns between familial patients with schizophrenia(FPS) and sporadic patients with schizophrenia(SPS). Ninety-eight patients with first-episode SZ(FPS=40, SPS=58) and 78 healthy controls were recruited. COMT gene was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Participants were scanned for 3.0T magnetic resonance images. Freesurfer software was used to analyze the difference in brain surface area between SZ and controls, its association with COMT genotypes, and the difference between SPS, FPS and control groups. Multiple tests were corrected using a Monte Carlo simulation at P<0.05. Compared with controls, SZ showed decreased surface area in right occipital cortex and left prefrontal cortex. No association was found between COMT polymorphisms and whole brain area difference. Among the three subgroups, SPS showed smaller left prefrontal area compared with both FPS and control groups. Patients with SPS also showed significant area reduction in right occipital lobe compared with controls. Surface area impairment can be found in those with first-episode SZ, but without association with COMT gene polymorphisms. The SPS have more severe area impairment than FPS, indicating that SPS and FPS may be attributed to different etiological mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 597 | Chronobiol. Int. 2015 Jun 32: 591-5 |
| PMID | 25798540 |
| Title | Differences in planning performance, a neurocognitive endophenotype, are associated with a functional variant in PER3 gene. |
| Abstract | Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive-compulsive disorder and Parkinson's disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian clock gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3-VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogotá, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p?=?0.003). These results appear to be independent from effects of this polymorphism on self-reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 598 | Schizophr. Res. 2015 May 164: 115-21 |
| PMID | 25728832 |
| Title | Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders. |
| Abstract | Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 599 | Biomed Res Int 2015 -1 2015: 829237 |
| PMID | 25722988 |
| Title | COMT-by-sex interaction effect on psychosis proneness. |
| Abstract | schizotypy phenotypes in the general population share etiopathogenic mechanisms and risk factors with schizophrenia, supporting the notion of psychosis as a continuum ranging from nonclinical to clinical deviance. Catechol-O-methyltransferase (COMT) is a candidate susceptibility gene for schizophrenia that is involved in the regulation of dopamine in the prefrontal cortex. Several recent studies have reported a sex difference in the impact of COMT genotype on psychiatric and cognitive phenotypes and personality traits. The present study investigated the association of COMT Val158Met (rs4680) with psychometric positive and negative schizotypy and psychotic experiences in a sample of 808 nonclinical young adults. The main finding was that sex moderates the association of COMT genotype with the negative dimension of both schizotypy and psychotic experiences. Male subjects carrying the Val allele tended to score higher on the negative dimension of both trait and symptom-like measures. The results from the present study are consistent with recent work suggesting an association between negative schizotypy and diminished prefrontal dopamine availability. They support the idea that a biological differentiation underlies the positive and negative schizotypy dimensions. Additionally, these findings contribute to the growing literature on sex-specific effects of COMT on the predisposition to psychiatric disorders and personality traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 600 | Neurosci Bull 2015 Feb 31: 31-42 |
| PMID | 25564193 |
| Title | Morphological changes in gray matter volume correlate with catechol-O-methyl transferase gene Val158Met polymorphism in first-episode treatment-naïve patients with schizophrenia. |
| Abstract | The catechol-O-methyltransferase (COMT) gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene, Val158/158Met, has been proposed to influence gray matter volume (GMV). However, the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study, we explored the relationship between the Val158Met polymorphism of the COMT gene and the GMV/cortical thickness/cortical surface area in 150 first-episode treatment-naïve patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual, medial temporal, parietal, and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover, a diagnosis × genotype interaction was found for the GMV of the left precuneus, and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition, a pattern of increased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia, and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 601 | Pharmacogenomics 2015 Jan 16: 35-44 |
| PMID | 25560469 |
| Title | COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine. |
| Abstract | Clozapine is still considered the gold standard for treatment-resistant schizophrenia patients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems. 107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMT rs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively. We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects. The findings support the hypothesis that COMT rs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 602 | Neurol. Sci. 2015 Feb 36: 215-20 |
| PMID | 25283873 |
| Title | COMT and STH polymorphisms interaction on cognition in schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) gene, a key regulator of prefrontal cortex (PFC) dopamine (DA) availability, has been extensively studied in relation to cognitive domains, mainly executive functions, that are impaired in schizophrenia, but results are still controversial. Since recent studies in patients affected by neurodegenerative and psychiatric disorders suggested a role of saitohin (STH) gene as a concurring factor in hypofrontality, we hypothesize that STH and COMT polymorphisms could have an additive effect on cognition in schizophrenia. Three forty three clinically stabilized patients with schizophrenia were assessed with a broad neuropsychological battery including the Brief Assessment of Cognition in schizophrenia, the Wisconsin Card Sorting Test and the Continuous Performance Test and were genotyped for COMT Val108/158Met and STH Q7R polymorphisms. We observed the effects of COMT on speed of processing and executive functions, as well as a significant effect of STH on executive functions performances. Moreover, a significant interaction between COMT and STH polymorphisms was found on executive functions, with COMT Val/Val and STH R carriers performing worse. Our results showed a significant interaction effect of COMT and STH polymorphisms on cognitive performances, strengthening the involvement of STH in cognitive impairments, especially in the domains commonly impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 603 | Psychopharmacology (Berl.) 2015 Jan 232: 145-54 |
| PMID | 25096017 |
| Title | Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia. |
| Abstract | Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 604 | CNS Neurol Disord Drug Targets 2015 -1 14: 1086-95 |
| PMID | 25801838 |
| Title | Association of Single Nucleotide Polymorphisms in Catechol-O-Methyltransferase and Serine-Threonine Protein Kinase Genes in the Pakistani Schizophrenic Population: A Study with Special Emphasis on Cannabis and Smokeless Tobacco. |
| Abstract | schizophrenia is a neuropsychiatric disorder in which abnormalities in the prefrontal cortex lead to impaired synthesis of dopamine. It is associated with hallucination, psychosis and hearing impairments. Many susceptible genes have been identified in schizophrenia such as catechol-O-methyltransferase (COMT) and serine/threonine kinase (AKT1). Single nucleotide polymorphisms (SNPs) in these genes have not been identified in Pakistan. Therefore, we investigated the allelic and genotypic frequencies in COMT and AKT1 genes in the Pakistani population. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used to identify SNPs in the genes. The present study shows that COMT Val and COMT Met allelic frequencies for the controls were p=0.52, q=0.48 and for the schizophrenic cases they were p=0.34, q=0.66 respectively. The distribution of polymorphism in COMT Val158Met genotype by Hardy-Weinberg equilibrium (HWE) was P=0.61 for controls and P=0.005 for cases. The data reveal that SNP rs1130214 T allele mutation was found neither in patients nor in controls in the 5' untranslated region (UTR). This proves that no association of AKT1 and positive association of COMT with schizophrenia exist in the population of Pakistan. Moreover, a study based on a single family showed COMT Met allele inheritance in schizophrenic offspring. This suggested that COMT allele alteration influences susceptibility to at least some forms of psychosis in the Pakistani population. Interestingly, according to our socio-economical survey, COMT genotype has no association with cannabis but it is strongly associated with tobacco. The Pakistani population with Val158Met SNP showed more susceptibility towards developing schizophrenia. This study highlights the genetic differences between Pakistani and other Caucasian populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 605 | Prilozi 2015 -1 36: 53-67 |
| PMID | 26076775 |
| Title | Pharmacogenetics and antipsychotic treatment response. |
| Abstract | (Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 606 | Neurosci Bull 2015 Feb 31: 31-42 |
| PMID | 25564193 |
| Title | Morphological changes in gray matter volume correlate with catechol-O-methyl transferase gene Val158Met polymorphism in first-episode treatment-naïve patients with schizophrenia. |
| Abstract | The catechol-O-methyltransferase (COMT) gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene, Val158/158Met, has been proposed to influence gray matter volume (GMV). However, the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study, we explored the relationship between the Val158Met polymorphism of the COMT gene and the GMV/cortical thickness/cortical surface area in 150 first-episode treatment-naïve patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual, medial temporal, parietal, and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover, a diagnosis × genotype interaction was found for the GMV of the left precuneus, and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition, a pattern of increased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia, and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 607 | Biomed Res Int 2015 -1 2015: 829237 |
| PMID | 25722988 |
| Title | COMT-by-sex interaction effect on psychosis proneness. |
| Abstract | schizotypy phenotypes in the general population share etiopathogenic mechanisms and risk factors with schizophrenia, supporting the notion of psychosis as a continuum ranging from nonclinical to clinical deviance. Catechol-O-methyltransferase (COMT) is a candidate susceptibility gene for schizophrenia that is involved in the regulation of dopamine in the prefrontal cortex. Several recent studies have reported a sex difference in the impact of COMT genotype on psychiatric and cognitive phenotypes and personality traits. The present study investigated the association of COMT Val158Met (rs4680) with psychometric positive and negative schizotypy and psychotic experiences in a sample of 808 nonclinical young adults. The main finding was that sex moderates the association of COMT genotype with the negative dimension of both schizotypy and psychotic experiences. Male subjects carrying the Val allele tended to score higher on the negative dimension of both trait and symptom-like measures. The results from the present study are consistent with recent work suggesting an association between negative schizotypy and diminished prefrontal dopamine availability. They support the idea that a biological differentiation underlies the positive and negative schizotypy dimensions. Additionally, these findings contribute to the growing literature on sex-specific effects of COMT on the predisposition to psychiatric disorders and personality traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 608 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2016 Jan 64: 87-95 |
| PMID | 26234518 |
| Title | Perception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex. |
| Abstract | Emotional facial stimuli are important social signals that are essential to be perceived and recognized in order to make appropriate decisions and responses in everyday communication. The ability to voluntarily guide attention to perceive and recognize emotions, and react to them varies largely across individuals, and has a strong genetic component (Friedman et al., 2008). Two key genetic variants of the catecholamine system that have been related to emotion perception and attention are the catechol-O-methyl transferase genetic variant (COMT Val158Met) and the ?2A-receptor gene promoter polymorphism (ADRA2A C-1291G) accordingly. So far, the interaction of the two with sex in emotion perception has not been studied. Multilevel modeling method was applied to study how COMT Val158Met, ADRA2A C-1291G and sex are associated with measures of emotion perception in a large sample of young adults. Participants (n=506) completed emotion recognition and behavioral emotion detection tasks. It was found that COMT Val158Met genotype in combination with the ADRA2A C-1291G and sex predicts emotion detection, and perception of valence and arousal. In simple visual detection, the ADRA2A C-1291G G-allele leads to slower detection of a highly arousing face (scheming), which is modulated by each additional COMT Val158Met Met-allele and male sex predicting faster responses. The combination of G-allele, Met-allele and male sex also predicts higher perceived negativity in sad faces. No effects of C-1291G, Val158Met, and sex were found on verbal emotion recognition. Applying the findings to study the interplay between catecholamine-O-methyl transferase activity and ?2A-receptors in emotion perception disorders (such as ADHD, autism and schizophrenia) in men and women would be the next step towards understanding individual differences in emotion perception. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 609 | Biol. Psychiatry 2016 Apr 79: 526-38 |
| PMID | 26970363 |
| Title | Human Laboratory Studies on Cannabinoids and Psychosis. |
| Abstract | Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 610 | Bioorg. Med. Chem. Lett. 2016 Jun 26: 2952-6 |
| PMID | 27133481 |
| Title | Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors. |
| Abstract | A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 611 | Behav. Brain Res. 2016 Mar 300: 123-34 |
| PMID | 26704217 |
| Title | Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats. |
| Abstract | schizophrenia-like symptoms were detected in vasopressin-deficient (di/di) Brattleboro rats, and it was also suggested that schizophrenia might have an epigenetic component. We aimed to clarify if epigenetic changes contribute to schizophrenia-like behavior of this strain. Behavioral (locomotion by telemetry, cognition by novel object recognition, social recognition and social avoidance test, attention by pre-pulse inhibition) and epigenetic differences were compared between wild type and di/di animals. DNA methyltransferase1 (DNMT1), DNMT3a, as well as COMT, GAD, VGLUT1, 5HT2A, BDNF mRNA levels in prefrontal brain region and hippocampus were studied by qRT-PCR. Histone3 (H3) and H4 acetylation (Ac) were studied by western-blot followed by region specific examination of H3 lysine9 (K9) acetylation by immunohistochemistry. Impaired cognitive, social and attention behavior of di/di rats confirmed schizophrenia-like symptoms in our local colony. The pan-AcH3 immunoreactivity was lower in prefrontal region and elevated in the hippocampus of di/di animals. We found lower immunopositive cell number in the dorsal peduncular prefrontal cortex and the ventral lateral septum and increased AcH3K9 immunoreactivity in CA1 region of di/di animals. There were no major significant alterations in the studied mRNA levels. We confirmed that Brattleboro rat is a good preclinical model of schizophrenia. Its schizophrenia-like behavioral alteration was accompanied by changes in H3 acetylation in the prefrontal region and hippocampus. This may contribute to disturbances of many schizophrenia-related substances leading to development of schizophrenia-like symptoms. Our studies confirmed that not a single gene, rather fine changes in an array of molecules are responsible for the majority of schizophrenia cases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 612 | Acta Neuropsychiatr 2016 Feb 28: 1-10 |
| PMID | 25877668 |
| Title | Transcranial direct current stimulation and neuroplasticity genes: implications for psychiatric disorders. |
| Abstract | Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders. A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms. Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials. Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 613 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Mar -1: -1 |
| PMID | 26954460 |
| Title | COMT genotype is associated with differential expression of muscarinic M1 receptors in human cortex. |
| Abstract | Catechol-O-methyltransferase (COMT) genotype has been associated with varying levels of cognitive functioning and an altered risk of schizophrenia. COMT regulates the breakdown of catecholamines, particularly dopamine, which is thought critical in maintaining cognitive function and the aetiology of schizophrenia. This hypothesis gained support from reports that the VAL allele at rs4680 was associated with poorer performance on cognitive tests and a slightly increased risk of schizophrenia. More recently, genotype at rs4818, part of a hapblock with rs4680, has been shown to impact on cognitive ability more than genotype at rs4680 but, as yet, not the risk for schizophrenia. Here, we determined if COMT genotype at rs4680 or rs4818, as well as rs165519 and rs737865, two synonymous single nucleotide polymorphisms (SNPs) with no known functional consequences, were associated with an altered risk of schizophrenia and if genotype at the four COMT SNPs was related to expression of the cortical muscarinic M1 receptor (CHRM1) because the expression of the cortical CHRM1 has been reported to be lower in schizophrenia and is important in maintaining cognitive functioning in humans. We report that the variation in gene sequence at the four COMT SNPs studied was not associated with an altered the risk of schizophrenia but genotype at rs4680 and rs4818, but not rs165519 and rs737865, were associated with varying levels of cortical CHRM1 expression in the human dorsolateral prefrontal cortex (DLPFC). These data are the first to suggest that levels of CHRM1 in the human DLPFC are, in part, determined by COMT gene sequence. © 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 614 | Transl Psychiatry 2016 -1 6: e824 |
| PMID | 27244233 |
| Title | A pilot study on commonality and specificity of copy number variants in schizophrenia and bipolar disorder. |
| Abstract | schizophrenia (SZ) and bipolar disorder (BD) are known to share genetic risks. In this work, we conducted whole-genome scanning to identify cross-disorder and disorder-specific copy number variants (CNVs) for these two disorders. The Database of Genotypes and Phenotypes (dbGaP) data were used for discovery, deriving from 2416 SZ patients, 592 BD patients and 2393 controls of European Ancestry, as well as 998 SZ patients, 121 BD patients and 822 controls of African Ancestry. PennCNV and Birdsuite detected high-confidence CNVs that were aggregated into CNV regions (CNVRs) and compared with the database of genomic variants for confirmation. Then, large (size?500?kb) and small common CNVRs (size <500?kb, frequency?1%) were examined for their associations with SZ and BD. Particularly for the European Ancestry samples, the dbGaP findings were further evaluated in the Wellcome Trust Case Control Consortium (WTCCC) data set for replication. Previously implicated variants (1q21.1, 15q13.3, 16p11.2 and 22q11.21) were replicated. Some cross-disorder variants were noted to differentially affect SZ and BD, including CNVRs in chromosomal regions encoding immunoglobulins and T-cell receptors that were associated more with SZ, and the 10q11.21 small CNVR (GPRIN2) associated more with BD. Disorder-specific CNVRs were also found. The 22q11.21 CNVR (COMT) and small CNVRs in 11p15.4 (TRIM5) and 15q13.2 (ARHGAP11B and FAN1) appeared to be SZ-specific. CNVRs in 17q21.2, 9p21.3 and 9q21.13 might be BD-specific. Overall, our primary findings in individual disorders largely echo previous reports. In addition, the comparison between SZ and BD reveals both specific and common risk CNVs. Particularly for the latter, differential involvement is noted, motivating further comparative studies and quantitative models. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 615 | Genet Test Mol Biomarkers 2016 May -1: -1 |
| PMID | 27228319 |
| Title | A Tetra-Primer Amplification Refractory System Technique for the Cost-Effective and Novel Genotyping of Eight Single-Nucleotide Polymorphisms of the Catechol-O-Methyltransferase Gene. |
| Abstract | Catechol-O-methyltransferase (COMT) is an enzyme involved in the degradation of catecholamine neurotransmitters. Due to its role in neurotransmitter flux, multiple COMT variants have been associated with the development of psychiatric disorders. Notably, select single-nucleotide polymorphisms (SNPs) of COMT have been implicated in schizophrenia risk, severity, and treatment response. In recognition of the value of a streamlined genotyping method for COMT SNP detection, this study was designed to develop a simple and economical tetra-primer amplification refractory mutation system (T-ARMS) assay for the concurrent detection of eight COMT SNPs: rs4680, rs737865, rs165599, rs2075507, rs4633, rs4818, rs6269, and rs165774. T-ARMS is a genotyping method that uses polymerase chain reaction (PCR) to amplify a multiplex reaction consisting of two primer pairs. T-ARMS primers are customized to each SNP and designed to generate different-sized allele-specific amplicons. This assay was applied to a total of 39 genomic DNA samples. Genotypic designations across the panel of SNPs were subsequently validated by Sanger sequencing. T-ARMS reliably and unambiguously detected all three genotypes (homozygous wild type, heterozygous, and homozygous mutant) for the eight COMT SNPs. Compared to traditional low-throughput methods that require post-PCR modification or high-throughput technologies that require sophisticated equipment, T-ARMS is a cost-effective and efficient assay that can be easily adapted by any standard molecular laboratory. This T-ARMS assay provides a practical and robust method for COMT SNP detection. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 616 | Encephale 2016 May -1: -1 |
| PMID | 27161263 |
| Title | [Stress and psychotic transition: A literature review]. |
| Abstract | Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress-vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis. The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans. We performed a bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'first episode psychosis', 'schizotypal', 'prodromal schizophrenia' in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles. Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs (i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset. The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 617 | Schizophr. Res. 2016 May 173: 94-100 |
| PMID | 27021555 |
| Title | COMT val158met polymorphism and molecular alterations in the human dorsolateral prefrontal cortex: Differences in controls and in schizophrenia. |
| Abstract | The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype and gene expression profile in the DLPFC of controls, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 618 | Neuromolecular Med. 2016 Jun 18: 216-31 |
| PMID | 27020768 |
| Title | The Role of a Catechol-O-Methyltransferase (COMT) Val158Met Genetic Polymorphism in Schizophrenia: A Systematic Review and Updated Meta-analysis on 32,816 Subjects. |
| Abstract | An association between a catechol-O-methyltransferase (COMT) Val156Met (rs4680) polymorphism and schizophrenia has been reported in the literature, although no conclusive outcomes have been attained. The aim of this study was to evaluate the association of the COMT Val108/158Met polymorphism with schizophrenia in a systematic review and meta-analysis. We performed a keyword search on PubMed and EBSCO databases. All English language case-control studies published up to April 2015 were selected. A total of 67 studies were selected for inclusion. The genotype distribution of subjects with schizophrenia was compared with healthy control subjects, using allelic, additive, dominant and recessive models. The pooled results from the meta-analysis (15,565 cases and 17,251 healthy subjects) after the elimination of heterogeneity showed an association between COMT Val108/158Met and schizophrenia [recessive model: OR 1.08 CI 95 % (1.01-1.15)]. We conducted subgroup analyses according to ethnicity. An association was observed in our Caucasian population in the additive model [OR 1.21 CI 95 % (1.06-1.37)] and in the recessive model [OR 1.21 CI 95 % (1.11-1.32)], but not in the allelic or dominant models. However, when we analysed our Asian population after the elimination of heterogeneity, no evidence of a significant association was found in any of the genetic models. Our analyses indicate that there is an association between COMT Val108/158Met and schizophrenia in the general population. Furthermore, in Caucasian populations, this risk could be increased. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 619 | Psychiatr. Genet. 2016 Mar -1: -1 |
| PMID | 26999687 |
| Title | The COMT Val158Met polymorphism moderates the association between cognitive functions and white matter microstructure in schizophrenia. |
| Abstract | Impaired cognitive functioning is a core feature of schizophrenia. Cognitive impairment in schizophrenia has been associated with white-matter (WM) abnormalities and degenerative changes of cortical myelin in the cerebral cortex. Furthermore, findings suggested a role of the COMT gene in affecting both WM and neuropsychological performances.We thus hypothesized that the COMT ValMet genotype would affect the association between cognitive functions and WM microstructure in a sample of schizophrenic patients. Seventy-eight schizophrenic patients performed the brief assessment of cognition in schizophrenia for assessment of cognitive performances. Sixty-nine patients provided a venous blood sample for genotypic analysis. WM integrity was evaluated using tract-based spatial statistics with threshold-free cluster enhancement (P<0.05). Analysis indicated an association between cognitive functions and WM microstructure in the Val/Val group, but not in the Met carriers group. WM tracts include the corpus callosum, thalamic radiations, corona radiata, forceps major and minor, superior and inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, and cingulum. Results suggested a moderating effect of the COMT ValMet polymorphism on the association between cognitive functioning and WM microstructure. Our findings support the importance of myelination in cognition, identifying measures of WM microstructure as important neurobiological features of cognitive performances. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 620 | Psychiatry Clin. Neurosci. 2016 Jun 70: 227-44 |
| PMID | 26969211 |
| Title | Biological aspects and candidate biomarkers for psychotic bipolar disorder: A systematic review. |
| Abstract | We carried out a systematic review of the available literature about potential biomarkers of psychotic bipolar disorder (BD-P), a specific subset presenting worse outcome and greater risk of relapse than non-psychotic bipolar disorder (BD-NP). We searched the main psychiatric databases (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles with the main topic of BD-P compared to schizophrenia/BD-NP/healthy controls (HC) written in English from 1994 to 2015 were included. BD-P patients presented higher kynurenic acid levels in the cerebrospinal fluid, elevated anti- S accharomyces cerevisiae antibodies levels, and lower serum levels of dehydroepiandrosterone sulfate and progesterone than BD-NP/HC. Event-related potentials abnormalities have been identified in BD-P with respect to BD-NP. BD-P patients also presented bigger ventricles but similar hippocampal volumes compared to BD-NP/HC. Although the results are contrasting, some cognitive deficits seemed to be related to the psychotic dimension of bipolar affective disorder, such as impairment in verbal/logical memory, working memory, verbal and semantic fluency and executive functioning. Finally, polymorphisms of genes, such as NRG1, 5HTTLPR (s), COMT, DAOA and some chromosome regions (16p12 and 13q), were positively associated with BD-P. Data about the identification of specific biomarkers for BD-P are promising, but most of them have not yet been replicated. They could lead the clinicians to an early diagnosis and proper treatment, thus ameliorating outcome of BD-P and reducing the biological changes associated with a long duration of illness. Further studies with bigger samples are needed to detect more specific biological markers of the psychotic dimension of bipolar affective disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 621 | Neuroimage 2016 May 132: 556-70 |
| PMID | 26879624 |
| Title | Interaction between COMT Val(158)Met polymorphism and childhood adversity affects reward processing in adulthood. |
| Abstract | Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing. 168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. At reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 622 | Dev. Psychopathol. 2016 Feb -1: 1-14 |
| PMID | 26864886 |
| Title | Longitudinal study of premorbid adjustment in 22q11.2 deletion (velocardiofacial) syndrome and association with psychosis. |
| Abstract | Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome (22q11DS), is associated with an increased risk of major psychiatric disorders, including schizophrenia. The emergence of psychotic symptoms in individuals with schizophrenia in the general population is often preceded by a premorbid period of poor or worsening social and/or academic functioning. Our current study evaluated premorbid adjustment (via the Cannon-Spoor Premorbid Adjustment Scale [PAS]) and psychotic symptoms (via the Structured Interview for Prodromal Symptoms and the Kiddie Schedule for Affective Disorders and schizophrenia for School-Age Children-Present and Lifetime Version) in youth with 22q11DS (N = 96), unaffected siblings (N = 40), and community controls (N = 50). The PAS scores indicated greater maladjustment during all developmental periods in individuals with 22q11DS compared to the controls. Many participants with 22q11DS had chronically poor (n = 33) or deteriorating (n = 6) PAS scores. In 22q11DS, chronically poor PAS trajectories and poor childhood and early adolescence academic domain and total PAS scores significantly increased the risk of prodromal symptoms or overt psychosis. Taking into account the catechol-O-methyltransferase (COMT) genotype, the best predictor of (prodromal) psychosis was the early adolescence academic domain score, which yielded higher sensitivity and specificity in the subgroup of youth with 22q11DS and the high-activity (valine) allele. PAS scores may help identify individuals at higher risk for psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 623 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Apr 171: 447-57 |
| PMID | 26852906 |
| Title | Association of copy number polymorphisms at the promoter and translated region of COMT with Japanese patients with schizophrenia. |
| Abstract | Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 (?(2) ?=?8.327, P?=?0.0039), CNV6 (?(2) ?=?19.66, P?=?0.00005), and CNV8 (?(2) ?=?16.57, P?=?0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30?kb in COMT, may be genetic risk factors for schizophrenia. © 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 624 | Horm Mol Biol Clin Investig 2016 Mar 25: 157-70 |
| PMID | 26812880 |
| Title | Model approach for stress induced steroidal hormone cascade changes in severe mental diseases. |
| Abstract | Stress was described by Cushing and Selye as an adaptation to a foreign stressor by the anterior pituitary increasing ACTH, which stimulates the release of glucocorticoid and mineralocorticoid hormones. The question is raised whether stress can induce additional steroidal hormone cascade changes in severe mental diseases (SMD), since stress is the common denominator. A systematic literature review was conducted in PubMed, where the steroidal hormone cascade of patients with SMD was compared to the impact of increasing stress on the steroidal hormone cascade (a) in healthy amateur marathon runners with no overtraining; (b) in healthy well-trained elite soldiers of a ranger training unit in North Norway, who were under extreme physical and mental stress, sleep deprivation, and insufficient calories for 1 week; and, (c) in soldiers suffering from post traumatic stress disorder (PTSD), schizophrenia (SI), and bipolar disorders (BD). (a) When physical stress is exposed moderately to healthy men and women for 3-5 days, as in the case of amateur marathon runners, only few steroidal hormones are altered. A mild reduction in testosterone, cholesterol and triglycerides is detected in blood and in saliva, but there was no decrease in estradiol. Conversely, there is an increase of the glucocorticoids, aldosterone and cortisol. Cellular immunity, but not specific immunity, is reduced for a short time in these subjects. (b) These changes are also seen in healthy elite soldiers exposed to extreme physical and mental stress but to a somewhat greater extent. For instance, the aldosterone is increased by a factor of three. (c) In SMD, an irreversible effect on the entire steroidal hormone cascade is detected. Hormones at the top of the cascade, such as cholesterol, dehydroepiandrosterone (DHEA), aldosterone and other glucocorticoids, are increased. However, testosterone and estradiol and their metabolites, and other hormones at the lower end of the cascade, seem to be reduced. 1) The rate and extent of reduction of the androgen metabolites may cause a decrease of cellular and specific immunity which can lead to viral and bacterial infections; joint and stomach inflammation; general pain; and allergic reactions. 2) The decrease in testosterone, and estradiol in SMD may have detrimental effects in cell repair as the estradiol metabolite, 2-methoxy-estradiol (2ME2), helps to transforms stem cells into functional cells. As dopamine and 2ME2 are inversely metabolized via various forms of catechol-O-methyl transferase (COMT), well-being and hypertension may be related. 2ME2 is related to vascular endothelial growth factor (VEGF), which regulates blood capillary growth and O2 supply. As reduced O2 is a key marker of stress, the increase of glucocorticoids in all forms of mental and physical stress cannot counterbalance the reduced 2ME2 in cellular and mental stress. The increased cholesterol and triglycerides are related to stroke and infarction, contributing to a reduced life expectancy in SMD between 14 and 20 years. The increase of aldosterone leads to increases in anxiety, edema, and lung infections. Increasing mental and physical stress is related to systematic deviations in the steroidal hormone cascade in the non-psychotic state, which then may cause life threatening co-morbidities in PTSD, SI, and BD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 625 | Int. J. Neuropsychopharmacol. 2016 May 19: -1 |
| PMID | 26745992 |
| Title | Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. |
| Abstract | The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study's original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 626 | Psychoneuroendocrinology 2016 Mar 65: 67-75 |
| PMID | 26724569 |
| Title | Catechol-O-methyltransferase gene variants may associate with negative symptom response and plasma concentrations of prolactin in schizophrenia after amisulpride treatment. |
| Abstract | Catechol-O-methyltransferase (COMT) enzyme is involved in the pathogenesis of psychotic symptoms and may be associated with a therapeutic response to antipsychotic drugs. The aim of this study was to examine the relationship between COMT variants, plasma prolactin level, and the therapeutic effectiveness of amisulpride treatment in patients with schizophrenia. A 12-week naturalistic study of amisulpride treatment was carried out in 185 Han Chinese patients with schizophrenia. The patients were screened for 14 single-nucleotide polymorphisms of the COMT gene. The Positive and Negative Syndrome Scale (PANSS) was used to assess the improvement of psychopathological symptoms from the baseline to the end point in each subject. For better presentation of time-course changes in response status, a mixed model for repeated-measures (MMRM) analysis of symptom improvement during the 12-week treatment period was conducted. The change in plasma prolactin level after amisulpride treatment was also examined (n=51). No significant differences in the genotype frequencies of the COMT variants investigated were observed between responders and non-responders. Moreover, an MMRM analysis of psychopathological symptom improvement during the 12-week treatment course showed that it depended significantly on COMT variants (rs4680, rs4633, and rs6267), particularly regarding changes in negative symptoms. The increase in plasma prolactin levels observed was influenced by the COMT rs4680 variant and was positively correlated with a reduction in PANSS negative scores. Our results suggest that variation of the COMT gene is associated with treatment response regarding negative symptoms and prolactin changes after amisulpride treatment in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 627 | Cortex 2016 Jan 74: 79-95 |
| PMID | 26649915 |
| Title | Is less really more: Does a prefrontal efficiency genotype actually confer better performance when working memory becomes difficult? |
| Abstract | Perhaps the most widely studied effect to emerge from the combination of neuroimaging and human genetics is the association of the COMT-Val(108/158)Met polymorphism with prefrontal activity during working memory. COMT-Val is a putative risk factor in schizophrenia, which is characterized by disordered prefrontal function. Work in healthy populations has sought to characterize mechanisms by which the valine (Val) allele may lead to disadvantaged prefrontal cognition. Lower activity in methionine (Met) carriers has been interpreted as advantageous neural efficiency. Notably, however, studies reporting COMT effects on neural efficiency have generally not reported working memory performance effects. Those studies have employed relatively low/easy working memory loads. Higher loads are known to elicit individual differences in working memory performance that are not visible at lower loads. If COMT-Met confers greater neural efficiency when working memory is easy, a reasonable prediction is that Met carriers will be better able to cope with increasing demand for neural resources when working memory becomes difficult. To our knowledge, this prediction has thus far gone untested. Here, we tested performance on three working memory tasks. Performance on each task was measured at multiple levels of load/difficulty, including loads more demanding than those used in prior studies. We found no genotype-by-load interactions or main effects of COMT genotype on accuracy or reaction time. Indeed, even testing for performance differences at each load of each task failed to find a single significant effect of COMT genotype. Thus, even if COMT genotype has the effects on prefrontal efficiency that prior work has suggested, such effects may not directly impact high-load working memory ability. The present findings accord with previous evidence that behavioral effects of COMT are small or nonexistent and, more broadly, with a growing consensus that substantial effects on phenotype will not emerge from candidate gene studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 628 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Apr 171: 325-32 |
| PMID | 26616111 |
| Title | Disorder-specific genetic factors in obsessive-compulsive disorder: A comprehensive meta-analysis. |
| Abstract | Much remains to be learned about the etiology of obsessive-compulsive disorder (OCD). Twin studies suggest that it arises from both disorder-specific and non-specific genetic factors. To understand the etiology of OCD per se, it is necessary to identify disorder-specific factors. Previous research shows that OCD is associated with serotonin-related polymorphisms (5-HTTLPR coded as triallelic and HTR2A rs6311/rs6313) and, in males, a polymorphism involved in catecholamine modulation; COMT (rs4680). The present study is the first comprehensive meta-analysis to investigate whether these polymorphisms are specific to OCD. A meta-analysis was conducted for genetic association studies of OCD or any other psychiatric disorder, published in any language, in any country. A total of 551 studies were examined, of which 290 were included, consisting of 47,358 cases and 68,942 controls from case control studies, and 2,443 trios from family based studies. The main meta-analysis was limited to those disorders in which there were at least five datasets (studies or sub-studies) per disorder. Results confirmed that OCD is associated with polymorphisms of 5-HTTLPR, HTR2A, and, in males only, COMT. These polymorphisms were not associated with almost all other forms of psychopathology, including unipolar mood disorders, bipolar disorder, panic disorder, schizophrenia, and alcohol dependence. OCD, compared to most other disorders, had a significantly stronger association with particular alleles of each of the polymorphisms. Results did not differ across ancestral groups (Asian vs. Caucasian), designs (case control vs. family based), or diagnostic systems. Results suggest that the polymorphisms investigated in this study are relatively specific to OCD. © 2015 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 629 | Neuroscientist 2016 Apr 22: 119-31 |
| PMID | 25686622 |
| Title | Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans? |
| Abstract | Language and communication through it are two of the defining features of normally developed human beings. However, both these functions are often impaired in autism and schizophrenia. In the former disorder, the problem usually emerges in early childhood (~2 years old) and typically includes a lack of communication. In the latter condition, the language problems usually occur in adolescence and adulthood and presents as disorganized speech. What are the fundamental mechanisms underlying these two disorders? Is there a shared genetic basis? Are the traditional beliefs about them true? Are there any common strategies for their prevention and management? To answer these questions, we searched PubMed by using autism, schizophrenia, gene, and language abnormality as keywords, and we reconsidered the basic concepts about these two diseases or syndromes. We found many functional genes, for example, FOXP2, COMT, GABRB3, and DISC1, are actually implicated in both of them. After observing the symptoms, genetic correlates, and temporal progression of these two disorders as well as their relationships more carefully, we now infer that the occurrence of these two diseases is likely developmentally regulated via interaction between the genome and the environment. Furthermore, we propose a unified view of autism and schizophrenia: a single age-dependently occurred disease that is newly named as Systemic Integral Disorder: if occurring in children before age 2, it is called autism; if in adolescence or a later age, it is called schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 630 | Brain Struct Funct 2016 Jan 221: 103-14 |
| PMID | 25319752 |
| Title | Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults. |
| Abstract | Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 631 | Transl Psychiatry 2016 -1 6: e738 |
| PMID | 26882038 |
| Title | AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers. |
| Abstract | Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis-which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content-and also ± 7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 632 | Encephale 2016 May -1: -1 |
| PMID | 27161263 |
| Title | [Stress and psychotic transition: A literature review]. |
| Abstract | Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress-vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis. The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans. We performed a bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'first episode psychosis', 'schizotypal', 'prodromal schizophrenia' in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles. Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs (i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset. The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 633 | Psychiatr. Genet. 2016 Mar -1: -1 |
| PMID | 26999687 |
| Title | The COMT Val158Met polymorphism moderates the association between cognitive functions and white matter microstructure in schizophrenia. |
| Abstract | Impaired cognitive functioning is a core feature of schizophrenia. Cognitive impairment in schizophrenia has been associated with white-matter (WM) abnormalities and degenerative changes of cortical myelin in the cerebral cortex. Furthermore, findings suggested a role of the COMT gene in affecting both WM and neuropsychological performances.We thus hypothesized that the COMT ValMet genotype would affect the association between cognitive functions and WM microstructure in a sample of schizophrenic patients. Seventy-eight schizophrenic patients performed the brief assessment of cognition in schizophrenia for assessment of cognitive performances. Sixty-nine patients provided a venous blood sample for genotypic analysis. WM integrity was evaluated using tract-based spatial statistics with threshold-free cluster enhancement (P<0.05). Analysis indicated an association between cognitive functions and WM microstructure in the Val/Val group, but not in the Met carriers group. WM tracts include the corpus callosum, thalamic radiations, corona radiata, forceps major and minor, superior and inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, and cingulum. Results suggested a moderating effect of the COMT ValMet polymorphism on the association between cognitive functioning and WM microstructure. Our findings support the importance of myelination in cognition, identifying measures of WM microstructure as important neurobiological features of cognitive performances. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 634 | Encephale 2016 May -1: -1 |
| PMID | 27161263 |
| Title | [Stress and psychotic transition: A literature review]. |
| Abstract | Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress-vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis. The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans. We performed a bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'first episode psychosis', 'schizotypal', 'prodromal schizophrenia' in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles. Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs (i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset. The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |