| 1 | Mol. Psychiatry 2000 May 5: 270-4 |
|---|---|
| PMID | 10889529 |
| Title | Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses. |
| Abstract | The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 2 | Pharmacogenomics 2000 Aug 1: 309-33 |
| PMID | 11256581 |
| Title | The DRD2 gene in psychiatric and neurological disorders and its phenotypes. |
| Abstract | The TaqIA D2 dopamine receptor (DRD2) minor (A1) allele was first associated with severe alcoholism a decade ago. Since then, studies both confirming and not confirmnning this finding were reported. However, a meta-analysis of a large number of Caucasian alcoholics (both more severe and less severe) and controls (both assessed and unassessed for substance use disorders) revealed a significantly higher frequency (p < 10(-6)) and prevalence (p < 10(-8)) of the DRD2 A1 allele in the alcoholics. Further analysis showed that the more severe alcoholics had a 3-fold higher prevalence of the DRD2 A1 allele than the assessed controls (p < 10(-10)), whereas no difference was found between the less severe alcoholics and the unassessed controls. DRD2 exonic or promoter mutations have not yet been associated with alcoholism, although two intronic variants at the TaqIB and intron 6 sites, which are in linkage disequilibrium with the TaqIA site, were associated with this disorder. Variants of the DRD2 gene have also been associated with cocaine, nicotine and opioid dependence, obesity and gambling. It is hypothesised that the DRD2 is a reinforcement or reward gene. Although less intensively studied than substance use disorders, the DRD2 gene has been implicated in Tourette's syndrome (TS), post-traumatic stress disorder (PTSD) and certain symptoms associated with affective disorders and schizophrenia. Further, DRD2 variants have been implicated in Parkinson's disease (PD) and in iatrogenically-induced movement disorders, as well as in certain migraineurs. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in the brain of subjects who carry the DRD2 A1 allele. In addition, phenotypic differences have been found in neurocognitive and personality characteristics, and in treatment outcome of DRD2 variants. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the prevention and treatment of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 3 | Pharmacogenetics 2000 Jun 10: 335-41 |
| PMID | 10862524 |
| Title | The relationship between dopamine D2 receptor polymorphism at the Taq1 A locus and therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. |
| Abstract | Previous studies have demonstrated that subjects with one or two A1 alleles of dopamine D2 receptor (DRD2) polymorphism at the Taq1 A locus have lower DRD2 density than those with no A1 allele. The present study aimed to examine whether the Taq1 A DRD2 genotypes are related to therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. The subjects were 25 acutely exacerbated schizophrenic inpatients who had received no medication for at least 1 month before the study. The fixed dose (18 mg/day) of nemonapride was administered to each patient for 3 weeks. The clinical status was prospectively monitored by the Brief Psychiatric Rating Scale (BPRS) before, and 3 weeks after, the treatment. The Taq1 A genotypes (A1 and A2 alleles) were determined by the polymerase chain reaction method. Three patients were homozygous for the A1 allele, 11 were heterozygous for the A1 and A2 alleles, and 11 were homozygous for the A2 allele. The patients with one or two A1 alleles (n = 14) showed significantly higher percentage improvement in total BPRS and positive symptoms than those with no A1 allele (n = 11) after 3-week treatment while the percentage improvement in other subgrouped symptoms (negative, anxiety-depression, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the Taq1 A DRD2 polymorphism is related to early therapeutic response to nemonapride in schizophrenic patients, possibly by modifying the efficiency of DRD2 antagonism of the drug in the central nervous system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 4 | Psychopharmacology (Berl.) 2000 Apr 149: 246-50 |
| PMID | 10823405 |
| Title | Prolactin response to nemonapride, a selective antagonist for D2 like dopamine receptors, in schizophrenic patients in relation to Taq1A polymorphism of DRD2 gene. |
| Abstract | The dopamine D2 receptor (DRD2) gene has a Taq1A restriction fragment length polymorphism yielding two alleles, A1 and A2. It has been shown that the subjects with less frequent allele, the A1 allele, have lower density and diminished function of DRD2 in the striatum, compared to those with no A1 allele. In the present study, the relationship between this polymorphism and prolactin response to nemonapride, an antipsychotic drug with selective and potent DRD2 antagonistic property, was investigated in 25 Japanese schizophrenic inpatients (13 males, 12 females). The daily dose of nemonapride was fixed at 18 mg, and the duration of treatment was 3 weeks. Taq1A genotypes were determined by the polymerase chain reaction method. Plasma prolactin concentrations were measured by enzyme immunoassay. The subjects were divided into four subgroups by gender and Taq1A genotypes, i.e., six males and eight females with the A1 allele, seven males and four females with no A1 allele. The (delta)prolactin (change from the pretreatment concentration) at 1 week was significantly (P<0.05) higher in females with the A1 allele (78.0 +/- 47.1 ng/ml) than in males with the A1 allele (33.4 +/- 14.0 ng/ml) or with no A1 allele (29.5+/-24.8 ng/ml). In addition, (delta)prolactin at 3 weeks was significantly (P<0.05) higher in females with the A1 allele (98.1+/-67.9 ng/ml) than in females with no A1 allele (33.4+/-24.6 ng/ml), males with the A1 allele (29.1+/-17.3 ng/ml) or males with no A1 allele (28.6+/-22.0 ng/ml). The present study thus suggests that female patients with the A1 allele show a greater prolactin response to nemonapride, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 5 | Schizophr. Res. 2001 Apr 49: 65-71 |
| PMID | 11343865 |
| Title | Association study of schizophrenia with polymorphisms at six candidate genes. |
| Abstract | Clinical studies have shown that there is a genetic contribution to the pathogenesis of schizophrenia. The molecular mechanisms of effective antipsychotic drugs and recent advances in neural development suggest that several dopamine receptor, serotonin receptor and neurotrophic factor genes might be involved in the disorder. In this study, we assessed the associations between schizophrenia and polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3), the serotonin 2A receptor (5HTR2A), the brain-derived neurotrophic factor (BDNF), the ciliary neurotrophic factor (CNTF) and the neurotrophin-3 (NT-3) genes. Our results suggest that the polymorphisms at the DRD3, 5HTR2A, CNTF and BDNF gene loci are unlikely to make our sample more genetically susceptible to schizophrenia. However, we found significant differences in microsatellite allele frequencies between schizophrenic and control groups for DRD2 in the whole sample and for DRD2 and NT-3 only in women. Therefore, clinical differences in the presentation of schizophrenia between gender might be related to genetic factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 6 | Am. J. Med. Genet. 2001 Dec 105: 774-8 |
| PMID | 11803529 |
| Title | Association between three functional polymorphisms of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. |
| Abstract | The dopamine D2 receptor (DRD2) gene is considered one of the candidate genes contributing to the development of tardive dyskinesia (TD). In the present study, we investigated the genetic association between three functional polymorphisms (Ser311Cys, -141C Ins/Del and TaqI A) in the DRD2 gene and TD (200 patients with schizophrenia: 44 with TD and 156 without TD). No significant difference in the allelic and genotypic distribution between patients with TD and those without TD was observed. However, we found a slightly significant association between the -141C Ins/Del polymorphism and the total Abnormal Involuntary Movement Scale (AIMS) score (P = 0.037). The significant association between the -141C Ins/Del polymorphism and the total AIMS score did not remain after the regression analysis was taken into account (P = 0.14). Our results suggest that that three functional polymorphisms in DRD2 may not play a major role in the occurrence of TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 7 | Psychiatry Res 2001 Dec 105: 123-7 |
| PMID | 11740982 |
| Title | Lack of association between a polymorphism in the promoter region of the dopamine D2 receptor and personality traits. |
| Abstract | Disturbances of the dopaminergic neurotransmitter system have been associated with a personality trait that involves novelty seeking. A functional polymorphism in the promoter region of the dopamine D2 receptor gene (DRD2) has been reported to be associated with schizophrenia. We examined the association between this polymorphism in the DRD2 promoter region and personality traits, as assessed with the Tridimensional Personality Questionnaire. No significant association emerged between the polymorphism in the DRD2 promoter region and personality traits. Entering sex and age as covariates in an analysis of covariance did not change the results. These data fail to confirm an association between a polymorphism in the promoter region of the DRD2 and personality traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 8 | Am. J. Med. Genet. 2001 Mar 105: 176-8 |
| PMID | 11304833 |
| Title | Association analysis between two functional dopamine D2 receptor gene polymorphisms and schizophrenia. |
| Abstract | The dopamine D2 receptor (DRD2) gene has been listed as one of the candidate genes for susceptibility to schizophrenia. To date, a significant association between schizophrenia and two functional DRD2 gene polymorphisms, Ser311Cys and -141C Ins/Del, in Japanese samples, has been reported by Arinami et al. [1994: Lancet 343:703-704; 1997: Hum Mol Genet 6:577-582]. In the present study, we replicated the findings of Arinami et al. [1994: Lancet 343:703-704; 1997: Hum Mol Genet 6:577-582] in the same ethnic groups (Japanese samples) with the same polymorphisms (Ser311Cys and -141C Ins/Del). We genotyped these two polymorphisms for 241 patients and for 201 controls. Neither polymorphism was associated with schizophrenia. Moreover, in a haplotype analysis of the present sample, combined pairs of two polymorphisms provided no evidence for the association of either haplotype with schizophrenia. Our findings indicate that an association between the two functional DRD2 gene polymorphisms, Ser311Cys and -141C Ins/Del, and schizophrenia is unlikely. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 9 | Schizophr. Res. 2001 Apr 49: 65-71 |
| PMID | 11343865 |
| Title | Association study of schizophrenia with polymorphisms at six candidate genes. |
| Abstract | Clinical studies have shown that there is a genetic contribution to the pathogenesis of schizophrenia. The molecular mechanisms of effective antipsychotic drugs and recent advances in neural development suggest that several dopamine receptor, serotonin receptor and neurotrophic factor genes might be involved in the disorder. In this study, we assessed the associations between schizophrenia and polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3), the serotonin 2A receptor (5HTR2A), the brain-derived neurotrophic factor (BDNF), the ciliary neurotrophic factor (CNTF) and the neurotrophin-3 (NT-3) genes. Our results suggest that the polymorphisms at the DRD3, 5HTR2A, CNTF and BDNF gene loci are unlikely to make our sample more genetically susceptible to schizophrenia. However, we found significant differences in microsatellite allele frequencies between schizophrenic and control groups for DRD2 in the whole sample and for DRD2 and NT-3 only in women. Therefore, clinical differences in the presentation of schizophrenia between gender might be related to genetic factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 10 | Eur Arch Psychiatry Clin Neurosci 2001 -1 251: 57-9 |
| PMID | 11407439 |
| Title | Association between TaqI A dopamine D2 receptor polymorphism and therapeutic response to bromperidol: a preliminary report. |
| Abstract | The relationship between TaqI A dopamine D2 receptor (DRD2) polymorphism and therapeutic response to bromperidol, a selective dopamine antagonist, was investigated in 30 acutely exacerbated schizophrenic inpatients. Patients were treated with bromperidol 6-18 mg/day for 3 weeks. Clinical symptoms were evaluated by the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The TaqI A genotypes were determined with the PCR method. There was no significant difference in the percentage improvement of total BPRS or 5-subgrouped symptoms (positive, negative, anxiety-depression, excitement and cognitive symptoms) after the 3-week treatment between the patients with A1 alleles (n=18) and those with no A1 allele (n=12). Although the present study is preliminary, it is suggested that the TaqI A DRD2 polymorphism is not associated with therapeutic response to bromperidol in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 11 | Zh Nevrol Psikhiatr Im S S Korsakova 2001 -1 101: 50-3 |
| PMID | 11765615 |
| Title | [Dopamine receptor gene (DRD2) polymorphism in patients with endogenous psychoses with regard to their clinical heterogeneity]. |
| Abstract | Recently an association between genetic dopamine receptor gene (DRD2) polymorphism and schizophrenia was observed in several studies. In the current investigation we attempted to undertake further study of such association using an extended sample which comprised patients with schizophrenia (n = 184), schizoaffective psychosis (n = 63), affective disorders (n = 121)); healthy control subjects (n = 117) and first-degree relatives of the patients with psychoses who show no signs of mental diseases (n = 111). The genotypes A1A1, A1A2 and A2A2 and the relationship between Taq1DRD2 variants and some clinical symptoms and pathogenetic features of the patients with schizophrenia were studied. The results did not confirm the association between DRD2 genotype and any of disorders studied. But the A2A2 genotype frequency in the schizophrenic patient's group, with illness duration above 20 years and highly expressed positive, negative and psychopathological symptoms, increased significantly as compared to control group (73.7% vs 52.9%) and patients with less illness duration (73.7% vs 42.5%). In the latter case odds ratio was calculated as 4.12. In the light of this finding, A2A2 DRD2 genotype appears to be related to chronicity of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 12 | Pharmacogenetics 2001 Aug 11: 545-50 |
| PMID | 11505224 |
| Title | The -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients. |
| Abstract | Previous studies have demonstrated a lower density of dopamine D2 receptor (DRD2) in subjects without Del alleles of the -141C Ins/Del polymorphism in DRD2 gene promoter region than in those with one or two Del alleles. The present study aimed to examine whether the -141C Ins/Del DRD2 promoter polymorphism is related to therapeutic response to selective DRD2 antagonists in the treatment of schizophrenia. Subjects consisted of 49 acutely exacerbated schizophrenic inpatients treated with bromperidol (30 cases, mean dose +/- SD: 11.4 +/- 4.8 mg/day) or nemonapride (19 cases, 18 mg/day). Clinical symptoms were evaluated by the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The -141C Ins/Del DRD2 genotypes, the Ins and Del alleles, were determined by a polymerase chain reaction method. Thirty-five patients were homozygous for the Ins allele and 14 were heterozygous for the Del and Ins alleles. The patients without Del allele showed a higher percentage of improvement in anxiety-depression symptoms than those with Del allele (58.5 +/- 44.5% versus 24.1 +/- 48.2%) after 3 weeks of treatment while percentage improvement in total BPRS or other subgrouped symptoms (positive, negative, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the -141C Ins/Del DRD2 polymorphism is associated with anxiolytic and antidepressive effects of neuroleptic treatment in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 13 | Schizophr. Res. 2001 Apr 49: 203-12 |
| PMID | 11343878 |
| Title | Association and excess of transmission of a DRD2 haplotype in a sample of French schizophrenic patients. |
| Abstract | The gene which codes for dopamine receptor D2 (DRD2) is considered as one of the most relevant candidate genes in schizophrenia. Previous genetic studies focusing on this gene gave conflicting results, potentially because of the differences in methodology (linkage versus association studies), and the different loci analyzed (the DRD2 gene having many polymorphisms). We used a progressive strategy with three different approaches (case/control, haplotype relative risk and transmission disequilibrium test) and investigated two genetic polymorphisms (TaqI B1/B2 and TaqI A1/A2, spanning the coding region of the DRD2 gene) in 50 patients with DSM-IV diagnoses of schizophrenia, in their 100 parents and in 50 healthy, matched controls. Firstly, we found a significant excess of the two alleles (B2 and A2) in the schizophrenic group compared to unaffected controls. Secondly, we found an excess of transmission from the parents to their affected children, using the haplotype relative risk design applied to the B2A2 haplotype. Finally, the transmission disequilibrium test showed evidence for linkage between B2A2 haplotype and schizophrenia. The significant excess of the B2A2 haplotype in schizophrenic patients is specifically observed in a subsample of patients with a disease onset occurring after 20 years of age. As the haplotype contains nearly the entire DRD2 gene, we found convergent evidence in our sample for a significant role of the DRD2 gene in the risk for schizophrenia. This haplotype may be more specifically involved in the disorder's onset at a later age in some patients, or, alternatively, may be implicated as a modifying factor acting on age of onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 14 | Zh Nevrol Psikhiatr Im S S Korsakova 2001 -1 101: 50-3 |
| PMID | 11765615 |
| Title | [Dopamine receptor gene (DRD2) polymorphism in patients with endogenous psychoses with regard to their clinical heterogeneity]. |
| Abstract | Recently an association between genetic dopamine receptor gene (DRD2) polymorphism and schizophrenia was observed in several studies. In the current investigation we attempted to undertake further study of such association using an extended sample which comprised patients with schizophrenia (n = 184), schizoaffective psychosis (n = 63), affective disorders (n = 121)); healthy control subjects (n = 117) and first-degree relatives of the patients with psychoses who show no signs of mental diseases (n = 111). The genotypes A1A1, A1A2 and A2A2 and the relationship between Taq1DRD2 variants and some clinical symptoms and pathogenetic features of the patients with schizophrenia were studied. The results did not confirm the association between DRD2 genotype and any of disorders studied. But the A2A2 genotype frequency in the schizophrenic patient's group, with illness duration above 20 years and highly expressed positive, negative and psychopathological symptoms, increased significantly as compared to control group (73.7% vs 52.9%) and patients with less illness duration (73.7% vs 42.5%). In the latter case odds ratio was calculated as 4.12. In the light of this finding, A2A2 DRD2 genotype appears to be related to chronicity of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 15 | Pharmacogenetics 2001 Aug 11: 545-50 |
| PMID | 11505224 |
| Title | The -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients. |
| Abstract | Previous studies have demonstrated a lower density of dopamine D2 receptor (DRD2) in subjects without Del alleles of the -141C Ins/Del polymorphism in DRD2 gene promoter region than in those with one or two Del alleles. The present study aimed to examine whether the -141C Ins/Del DRD2 promoter polymorphism is related to therapeutic response to selective DRD2 antagonists in the treatment of schizophrenia. Subjects consisted of 49 acutely exacerbated schizophrenic inpatients treated with bromperidol (30 cases, mean dose +/- SD: 11.4 +/- 4.8 mg/day) or nemonapride (19 cases, 18 mg/day). Clinical symptoms were evaluated by the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The -141C Ins/Del DRD2 genotypes, the Ins and Del alleles, were determined by a polymerase chain reaction method. Thirty-five patients were homozygous for the Ins allele and 14 were heterozygous for the Del and Ins alleles. The patients without Del allele showed a higher percentage of improvement in anxiety-depression symptoms than those with Del allele (58.5 +/- 44.5% versus 24.1 +/- 48.2%) after 3 weeks of treatment while percentage improvement in total BPRS or other subgrouped symptoms (positive, negative, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the -141C Ins/Del DRD2 polymorphism is associated with anxiolytic and antidepressive effects of neuroleptic treatment in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 16 | Schizophr. Res. 2001 Apr 49: 203-12 |
| PMID | 11343878 |
| Title | Association and excess of transmission of a DRD2 haplotype in a sample of French schizophrenic patients. |
| Abstract | The gene which codes for dopamine receptor D2 (DRD2) is considered as one of the most relevant candidate genes in schizophrenia. Previous genetic studies focusing on this gene gave conflicting results, potentially because of the differences in methodology (linkage versus association studies), and the different loci analyzed (the DRD2 gene having many polymorphisms). We used a progressive strategy with three different approaches (case/control, haplotype relative risk and transmission disequilibrium test) and investigated two genetic polymorphisms (TaqI B1/B2 and TaqI A1/A2, spanning the coding region of the DRD2 gene) in 50 patients with DSM-IV diagnoses of schizophrenia, in their 100 parents and in 50 healthy, matched controls. Firstly, we found a significant excess of the two alleles (B2 and A2) in the schizophrenic group compared to unaffected controls. Secondly, we found an excess of transmission from the parents to their affected children, using the haplotype relative risk design applied to the B2A2 haplotype. Finally, the transmission disequilibrium test showed evidence for linkage between B2A2 haplotype and schizophrenia. The significant excess of the B2A2 haplotype in schizophrenic patients is specifically observed in a subsample of patients with a disease onset occurring after 20 years of age. As the haplotype contains nearly the entire DRD2 gene, we found convergent evidence in our sample for a significant role of the DRD2 gene in the risk for schizophrenia. This haplotype may be more specifically involved in the disorder's onset at a later age in some patients, or, alternatively, may be implicated as a modifying factor acting on age of onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 17 | Zh Nevrol Psikhiatr Im S S Korsakova 2001 -1 101: 48-50 |
| PMID | 11490436 |
| Title | [Molecular genetic polymorphism of the genes of neurotransmitter systems in schizophrenics with early manifestation of the disease]. |
| Abstract | Molecular-genetic polymorphism of genes-candidates was investigated: the genes of serotonin receptor--type 2a (HTR2A), dopamine receptor gene--type 2, serotonin transporter (5HTTLPR). Thirty one schizophrenic patients whose age was 12.6 +/- 3.6 years at the onset of the disease and 208 patients whose age was 23.5 +/- 6.7 years at the onset of the disease were examined. The frequencies of HTTLPR and DRD2 genotypes differed insignificantly in both groups. The distribution of 5HTR2A genotypes in the schizophrenic group with an early manifestation of the disease differed from that with a later manifestation significantly (chi 2 = 6.27; df = 2; p = 0.044). The relative risk (odds ratios) was 7.9 with 95% significance interval 1.008-61.94; p = 0.045. The severity of the disease and a positive family history were also examined in A2A2 genotype carriers. A positive family history was found in 9 (52.9%) of the 17 schizophrenics with an early manifestation and only in 15 (21.1%) of 71 patients of the similar group with a later one. Assessment of the clinical symptoms revealed that the total scores by the negative symptomatology subscale (PANSS) was higher in the patients with an early manifestation than in those with later one; but these differences did not achieve the significance level. These and earlier findings lead to the conclusion that A2A2 genotype was more frequently observed in the patients with more pronounced negative symptoms and high hereditary burden, which suggests that the A2A2 genotype is associated with an early onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 18 | Zh Nevrol Psikhiatr Im S S Korsakova 2001 -1 101: 48-50 |
| PMID | 11490436 |
| Title | [Molecular genetic polymorphism of the genes of neurotransmitter systems in schizophrenics with early manifestation of the disease]. |
| Abstract | Molecular-genetic polymorphism of genes-candidates was investigated: the genes of serotonin receptor--type 2a (HTR2A), dopamine receptor gene--type 2, serotonin transporter (5HTTLPR). Thirty one schizophrenic patients whose age was 12.6 +/- 3.6 years at the onset of the disease and 208 patients whose age was 23.5 +/- 6.7 years at the onset of the disease were examined. The frequencies of HTTLPR and DRD2 genotypes differed insignificantly in both groups. The distribution of 5HTR2A genotypes in the schizophrenic group with an early manifestation of the disease differed from that with a later manifestation significantly (chi 2 = 6.27; df = 2; p = 0.044). The relative risk (odds ratios) was 7.9 with 95% significance interval 1.008-61.94; p = 0.045. The severity of the disease and a positive family history were also examined in A2A2 genotype carriers. A positive family history was found in 9 (52.9%) of the 17 schizophrenics with an early manifestation and only in 15 (21.1%) of 71 patients of the similar group with a later one. Assessment of the clinical symptoms revealed that the total scores by the negative symptomatology subscale (PANSS) was higher in the patients with an early manifestation than in those with later one; but these differences did not achieve the significance level. These and earlier findings lead to the conclusion that A2A2 genotype was more frequently observed in the patients with more pronounced negative symptoms and high hereditary burden, which suggests that the A2A2 genotype is associated with an early onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 19 | Am. J. Med. Genet. 2001 Apr 105: 271-4 |
| PMID | 11353448 |
| Title | Relationship between Taq1 A dopamine D2 receptor (DRD2) polymorphism and prolactin response to bromperidol. |
| Abstract | The dopamine D2 receptor (DRD2) gene has a Taq1 A restriction fragment length polymorphism yielding two alleles, A1 and A2. We have previously shown that female patients with the A1 allele show greater prolactin response to nemonapride, a selective antagonist for D2-like dopamine receptors, in schizophrenic patients. In the present study, the relationship between this polymorphism and prolactin response to bromperidol was investigated in 32 untreated schizophrenic inpatients (16 males, 16 females). The daily dose of bromperidol was fixed at 6 (n = 10), 12 (n = 13), or 18 mg (n = 9) during a 2-week treatment period. Taq1 A genotypes were determined by PCR method. Plasma prolactin concentration was measured by radioimmunoassay. Plasma concentration of bromperidol was measured by HPLC method. The subjects were divided into four subgroups by gender and the genotypes, i.e., 10 males and 11 females with the A1 allele, 6 males and 5 females with no A1 allele. The females with the A1 allele had the highest Delta prolactin (the change from the pretreatment concentration)/bromperidol concentration ratio among the other groups (P < 0.05). The present study thus suggests that female patients with the A1 allele show greater prolactin response to bromperidol, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 20 | Psychiatry Res 2001 Feb 101: 33-8 |
| PMID | 11223117 |
| Title | No relationship between--141C Ins/Del polymorphism in the promoter region of dopamine D2 receptor and extrapyramidal adverse effects of selective dopamine D2 antagonists in schizophrenic patients: a preliminary study. |
| Abstract | Previous studies have shown that subjects without Del alleles of the--141C Ins/Del polymorphism in the promoter region of the dopamine D2 receptor (DRD2) gene have lower DRD2 density that those with one or two Del alleles. The present study aims to investigate the relationship between the -141C Ins/Del polymorphism and extrapyramidal adverse effects of bromperidol and nemonapride, antipsychotic drugs with a selective and potent DRD2 antagonistic property, in schizophrenic inpatients. Twenty-seven patients were treated with bromperidol at a fixed-dose of 6, 12 or 18 mg/day, and 25 patients were treated with nemonapride at a fixed-dose of 18 mg/day. The duration of treatment with these drugs was 3 weeks. The Ins and Del alleles were determined by PCR. Extrapyramidal adverse effects were assessed by the Udvalg for Kliniske Undersøgelser side effects rating scale. The subjects consisted of 38 homozygotes of the Ins allele and 14 heterozygotes of the Ins and Del alleles. There were no significant differences in the incidence or severity of extrapyramidal adverse effects between patients with and without the Del allele. It is possible that this result was due to a lack of statistical power. However, the present study suggests that the--141C Ins/Del polymorphism is not related to the development of extrapyramidal adverse effects during acute-phase treatment with antidopaminergic agents. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 21 | Mol. Psychiatry 2002 -1 7: 1002-5 |
| PMID | 12399954 |
| Title | Association and linkage disequilibrium between a functional polymorphism of the dopamine-2 receptor gene and schizophrenia in a genetically homogeneous Portuguese population. |
| Abstract | A functional polymorphism in the promoter region of the DRD2 gene has been found to be associated with schizophrenia in Japanese(1,2) and Swedish populations.(3) We attempted to replicate these findings in a genetically homogeneous Portuguese population using a family-based study design. Analysis of 78 trios revealed evidence for association between the -141 C Ins allele and schizophrenia using the haplotype relative risk (HRR) method (chi(2) = 9.30, P = 0.0023). Further examination of this sample using an alternative family-based association analysis method, the transmission disequilibrium test (TDT), of 33 informative matings from the Portuguese trios provided evidence for an allelic association and linkage disequilibrium between the insertion allele and schizophrenia (chi(2) = 8.76, P = 0.0031). These consistent results using two alternative family-based association analysis methods replicate the findings of previous reports, and thus further implicate a potential role for the dopamine-2 receptor in the genetic etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 22 | Am. J. Med. Genet. 2002 Aug 114: 593-7 |
| PMID | 12210271 |
| Title | Gender-specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia. |
| Abstract | We examined the genetic effect of DRD2 A1 allele in 167 Korean schizophrenics in relation to their smoking habit. Although there was no apparent difference in the genotype distributions of DRD2 gene among the female schizophrenics (n = 66), the male counterpart (n = 101) showed significant differences in their genotype distributions. The comparison between male smoking and non-smoking patients showed the difference in genotype distribution (P = 0.010) with a higher prevalence of A1 allele (P = 0.020) and frequency of heterozygotes (P = 0.005), but not frequency of the A1 allele. The A1A2 heterozygotes male showed significantly higher smoking rate compared to the A1A1 or A2A2 homozygotes male, and non-smokers were deficient in heterozygotes. By contrast, among female schizophrenics, the heterozygotes showed a lower smoking rate than homozygotes and there were more heterozygotes in non-smokers. The deviation from Hardy-Weinberg expectations was observed in male and female non-smokers showing quite opposite profiles. Highly significant differences were seen between male and female non-smokers in A1 prevalence (P = 0.001), genotype distribution (P = 0.00011), and frequency of heterozygotes (P = 0.00003), but not in A1 frequency. The analyses from both male and female as one group showing no significant difference in the genotype distributions between smokers and non-smokers could be explained by the gender difference in the genetic effect of DRD2 A1 allele. Our findings present the gender-specific molecular heterosis of DRD2 gene in relation specifically to the smoking status of schizophrenic patients. They indicate the importance of heterosis and gender effects that should be taken into consideration for the association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 23 | Mol. Psychiatry 2002 -1 7: 695-705 |
| PMID | 12192613 |
| Title | Relationship between adverse effects of antipsychotic treatment and dopamine D(2) receptor polymorphisms in patients with schizophrenia. |
| Abstract | Extrapyramidal adverse symptoms (EPS) represent a major type of adverse events in treatment with typical antipsychotic drugs which share high affinity to the dopamine D(2) receptor (DRD2). Genetic variants of this receptor may modulate the therapeutic response and the severity of adverse symptoms of antipsychotics. We analyzed nine known polymorphisms of the DRD2 in 665 schizophrenic patients with European Caucasian ethnic background and compared the intensity of acute dystonia, extrapyramidal symptoms, akathisia, and tardive dyskinesia between carriers of different DRD2 genotypes. In a subgroup of 40 patients with most severe extrapyramidal symptoms we sequenced the coding region including the exon-intron junctions of the DRD2 gene. Functionally relevant DRD2 amino acid variants (Ser(310), Cys(311)) were rare or were not found at all (Ala(96)). Complete sequence analysis of sufferers from the most severe adverse effects revealed two new intronic polymorphisms and a silent polymorphism in exon 7, but no new amino acid variants beyond those which are already known. We found no significant association between these polymorphisms and the intensity of the different types of adverse neurologic effects of the antipsychotics. These results were obtained by correlating adverse events with each of the nine single nucleotide polymorphisms and by correlation with the estimated haplotypes. In conclusion, genetic variations in the DRD2 gene were no major predictors of the individually variable adverse effects from antipsychotic treatment in Caucasian schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 24 | Neuropsychopharmacology 2002 Jun 26: 794-801 |
| PMID | 12007750 |
| Title | Delusional disorder: molecular genetic evidence for dopamine psychosis. |
| Abstract | Since delusional disorder is characterized by mono-symptomatic paranoid symptoms, it can be a good clinical model for investigating the dopaminergic mechanism responsible for paranoid symptoms. We examined neuroleptic responses, plasma homovanillic acid (pHVA) and genes of the dopamine receptor (DR) and its synthesizing enzyme (tyrosine hydroxylase: TH) in patients with delusional disorder and compared them with those of schizophrenic patients and healthy controls. (1) A relatively small dose of haloperidol was more effective for delusional disorder than for schizophrenia. (2) The pretreatment level of pHVA was higher in patients with persecution-type, but not in those with jealousy-type delusional disorder, compared with age- and sex-matched controls. This increased pHVA level was decreased eight weeks after successful haloperidol treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%). (4) Patients homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA than those heterozygous for Ser9Gly. (v) A significant positive correlation was found between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder. We suggest that delusional disorder, especially the persecution-type, includes a "dopamine psychosis," and that polymorphism of the DRD2, DRD3 and/or TH gene is part of the genetic basis underlying the hyperdopaminergic state that produces paranoid symptoms. Further studies on a large sample size are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 25 | Psychiatry Clin. Neurosci. 2002 Feb 56: 97-102 |
| PMID | 11929577 |
| Title | The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms. |
| Abstract | The hyperactivity of dopaminergic systems is one of the major etiological hypotheses of schizophrenia. The major support for this hypothesis is that effective antipsychotic drugs bind to dopamine receptors and improve acute schizophrenic symptoms. For this reason, we investigated the allelic association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. The subjects were 190 schizophrenics (120 males and 70 females) and 103 normal controls (53 males and 50 females). There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no statistical association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. These results indicate that the DRD2 gene may not develop schizophrenia. Next, we examined whether the genotypes influence the symptoms of schizophrenia the using Positive and Negative Symptom Scale scores. The Ser/Cys patients exhibited significantly lower positive and negative symptom scores than Ser/Ser patients. Patients with Del/Del, Ins/Del, or Ins/Ins showed higher positive symptom scores in descending order. This result suggested that the Del allele worsens the positive symptoms. We concluded that the DRD2 receptor gene may not influence the onset of schizophrenia, but there is a strong possibility that the Cys311 and -141C Del have a significant influence on the symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 26 | Am. J. Med. Genet. 2002 Aug 114: 593-7 |
| PMID | 12210271 |
| Title | Gender-specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia. |
| Abstract | We examined the genetic effect of DRD2 A1 allele in 167 Korean schizophrenics in relation to their smoking habit. Although there was no apparent difference in the genotype distributions of DRD2 gene among the female schizophrenics (n = 66), the male counterpart (n = 101) showed significant differences in their genotype distributions. The comparison between male smoking and non-smoking patients showed the difference in genotype distribution (P = 0.010) with a higher prevalence of A1 allele (P = 0.020) and frequency of heterozygotes (P = 0.005), but not frequency of the A1 allele. The A1A2 heterozygotes male showed significantly higher smoking rate compared to the A1A1 or A2A2 homozygotes male, and non-smokers were deficient in heterozygotes. By contrast, among female schizophrenics, the heterozygotes showed a lower smoking rate than homozygotes and there were more heterozygotes in non-smokers. The deviation from Hardy-Weinberg expectations was observed in male and female non-smokers showing quite opposite profiles. Highly significant differences were seen between male and female non-smokers in A1 prevalence (P = 0.001), genotype distribution (P = 0.00011), and frequency of heterozygotes (P = 0.00003), but not in A1 frequency. The analyses from both male and female as one group showing no significant difference in the genotype distributions between smokers and non-smokers could be explained by the gender difference in the genetic effect of DRD2 A1 allele. Our findings present the gender-specific molecular heterosis of DRD2 gene in relation specifically to the smoking status of schizophrenic patients. They indicate the importance of heterosis and gender effects that should be taken into consideration for the association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 27 | Am. J. Med. Genet. 2002 Aug 114: 593-7 |
| PMID | 12210271 |
| Title | Gender-specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia. |
| Abstract | We examined the genetic effect of DRD2 A1 allele in 167 Korean schizophrenics in relation to their smoking habit. Although there was no apparent difference in the genotype distributions of DRD2 gene among the female schizophrenics (n = 66), the male counterpart (n = 101) showed significant differences in their genotype distributions. The comparison between male smoking and non-smoking patients showed the difference in genotype distribution (P = 0.010) with a higher prevalence of A1 allele (P = 0.020) and frequency of heterozygotes (P = 0.005), but not frequency of the A1 allele. The A1A2 heterozygotes male showed significantly higher smoking rate compared to the A1A1 or A2A2 homozygotes male, and non-smokers were deficient in heterozygotes. By contrast, among female schizophrenics, the heterozygotes showed a lower smoking rate than homozygotes and there were more heterozygotes in non-smokers. The deviation from Hardy-Weinberg expectations was observed in male and female non-smokers showing quite opposite profiles. Highly significant differences were seen between male and female non-smokers in A1 prevalence (P = 0.001), genotype distribution (P = 0.00011), and frequency of heterozygotes (P = 0.00003), but not in A1 frequency. The analyses from both male and female as one group showing no significant difference in the genotype distributions between smokers and non-smokers could be explained by the gender difference in the genetic effect of DRD2 A1 allele. Our findings present the gender-specific molecular heterosis of DRD2 gene in relation specifically to the smoking status of schizophrenic patients. They indicate the importance of heterosis and gender effects that should be taken into consideration for the association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 28 | Mol. Psychiatry 2002 -1 7: 695-705 |
| PMID | 12192613 |
| Title | Relationship between adverse effects of antipsychotic treatment and dopamine D(2) receptor polymorphisms in patients with schizophrenia. |
| Abstract | Extrapyramidal adverse symptoms (EPS) represent a major type of adverse events in treatment with typical antipsychotic drugs which share high affinity to the dopamine D(2) receptor (DRD2). Genetic variants of this receptor may modulate the therapeutic response and the severity of adverse symptoms of antipsychotics. We analyzed nine known polymorphisms of the DRD2 in 665 schizophrenic patients with European Caucasian ethnic background and compared the intensity of acute dystonia, extrapyramidal symptoms, akathisia, and tardive dyskinesia between carriers of different DRD2 genotypes. In a subgroup of 40 patients with most severe extrapyramidal symptoms we sequenced the coding region including the exon-intron junctions of the DRD2 gene. Functionally relevant DRD2 amino acid variants (Ser(310), Cys(311)) were rare or were not found at all (Ala(96)). Complete sequence analysis of sufferers from the most severe adverse effects revealed two new intronic polymorphisms and a silent polymorphism in exon 7, but no new amino acid variants beyond those which are already known. We found no significant association between these polymorphisms and the intensity of the different types of adverse neurologic effects of the antipsychotics. These results were obtained by correlating adverse events with each of the nine single nucleotide polymorphisms and by correlation with the estimated haplotypes. In conclusion, genetic variations in the DRD2 gene were no major predictors of the individually variable adverse effects from antipsychotic treatment in Caucasian schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 29 | Neuropsychopharmacology 2002 Jun 26: 794-801 |
| PMID | 12007750 |
| Title | Delusional disorder: molecular genetic evidence for dopamine psychosis. |
| Abstract | Since delusional disorder is characterized by mono-symptomatic paranoid symptoms, it can be a good clinical model for investigating the dopaminergic mechanism responsible for paranoid symptoms. We examined neuroleptic responses, plasma homovanillic acid (pHVA) and genes of the dopamine receptor (DR) and its synthesizing enzyme (tyrosine hydroxylase: TH) in patients with delusional disorder and compared them with those of schizophrenic patients and healthy controls. (1) A relatively small dose of haloperidol was more effective for delusional disorder than for schizophrenia. (2) The pretreatment level of pHVA was higher in patients with persecution-type, but not in those with jealousy-type delusional disorder, compared with age- and sex-matched controls. This increased pHVA level was decreased eight weeks after successful haloperidol treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%). (4) Patients homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA than those heterozygous for Ser9Gly. (v) A significant positive correlation was found between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder. We suggest that delusional disorder, especially the persecution-type, includes a "dopamine psychosis," and that polymorphism of the DRD2, DRD3 and/or TH gene is part of the genetic basis underlying the hyperdopaminergic state that produces paranoid symptoms. Further studies on a large sample size are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 30 | Psychiatry Clin. Neurosci. 2002 Feb 56: 97-102 |
| PMID | 11929577 |
| Title | The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms. |
| Abstract | The hyperactivity of dopaminergic systems is one of the major etiological hypotheses of schizophrenia. The major support for this hypothesis is that effective antipsychotic drugs bind to dopamine receptors and improve acute schizophrenic symptoms. For this reason, we investigated the allelic association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. The subjects were 190 schizophrenics (120 males and 70 females) and 103 normal controls (53 males and 50 females). There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no statistical association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. These results indicate that the DRD2 gene may not develop schizophrenia. Next, we examined whether the genotypes influence the symptoms of schizophrenia the using Positive and Negative Symptom Scale scores. The Ser/Cys patients exhibited significantly lower positive and negative symptom scores than Ser/Ser patients. Patients with Del/Del, Ins/Del, or Ins/Ins showed higher positive symptom scores in descending order. This result suggested that the Del allele worsens the positive symptoms. We concluded that the DRD2 receptor gene may not influence the onset of schizophrenia, but there is a strong possibility that the Cys311 and -141C Del have a significant influence on the symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 31 | Psychiatry Clin. Neurosci. 2002 Feb 56: 97-102 |
| PMID | 11929577 |
| Title | The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms. |
| Abstract | The hyperactivity of dopaminergic systems is one of the major etiological hypotheses of schizophrenia. The major support for this hypothesis is that effective antipsychotic drugs bind to dopamine receptors and improve acute schizophrenic symptoms. For this reason, we investigated the allelic association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. The subjects were 190 schizophrenics (120 males and 70 females) and 103 normal controls (53 males and 50 females). There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no statistical association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. These results indicate that the DRD2 gene may not develop schizophrenia. Next, we examined whether the genotypes influence the symptoms of schizophrenia the using Positive and Negative Symptom Scale scores. The Ser/Cys patients exhibited significantly lower positive and negative symptom scores than Ser/Ser patients. Patients with Del/Del, Ins/Del, or Ins/Ins showed higher positive symptom scores in descending order. This result suggested that the Del allele worsens the positive symptoms. We concluded that the DRD2 receptor gene may not influence the onset of schizophrenia, but there is a strong possibility that the Cys311 and -141C Del have a significant influence on the symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 32 | 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 |
| 33 | Mol. Psychiatry 2003 Nov 8: 911-5 |
| PMID | 14593428 |
| Title | Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia. |
| Abstract | The D2 subtype of dopamine receptor has been widely implicated in the pathogenesis of schizophrenia. Early evidence supporting an association between the Cys311Ser polymorphism of the D2 receptor gene (DRD2) and schizophrenia was subsequently refuted and, eventually, dismissed. From all 24 published case-control studies, we calculated a pooled estimate of this association. The pooled odds ratio was 1.3 for the Cys allele, which was highly significant (P=0.007). The odds ratio derived from each study was unrelated to the ethnicity or gender composition of the sample, or the age of the control group. There was no evidence of publication bias or excessive influence attributable to any given study. Although more family-based studies are needed to confirm this relation, our results provide strong evidence that DRD2 influences susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 34 | Pharmacogenomics J. 2003 -1 3: 277-83 |
| PMID | 14583797 |
| Title | Association of dopaminergic and serotonergic genes with tardive dyskinesia in patients with chronic schizophrenia. |
| Abstract | Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 35 | Neurosci. Behav. Physiol. 2003 Mar 33: 223-5 |
| PMID | 12762588 |
| Title | Analysis of the linkage of the Taq1A and Taq1B loci of the dopamine D2 receptor gene with schizophrenia in patients and their siblings. |
| Abstract | The linkage of the polymorphous markers Taq1A and Taq1B of the DRD2 dopamine receptor gene, located in region 11q22-11q23 of chromosome 11, with schizophrenia was studied. The investigation involved 29 complete families containing concordant and discordant sibling pairs. Common alleles at locus Taq1A were found significantly more frequently in concordant pairs (p = 0.04), and there was a tendency to a higher frequency of transmission of the maternal allele as compared with the paternal allele (p = 0.06). No such relationships were seen in the case of the Taq1B locus. Neither locus showed any significant difference in the frequency of common alleles in discordant pairs or in the predominance of allele transmission from one of the parents. These data demonstrate a possible linkage with schizophrenia for the Taq1A marker but not for the Taq1B marker. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 36 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 28-34 |
| PMID | 12707934 |
| Title | Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: association study and meta-analysis. |
| Abstract | An association has been reported between a dopamine D(2) receptor gene (DRD2) Ser311Cys variant and schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 173) and control subjects (n = 236) were assessed for the DRD2 Ser311Cys variant. schizophrenic patients displayed higher Cys311 allele frequencies than control subjects (4.0 vs. 0.8%, chi(2) = 9.49, df = 1, P = 0.002; odds ratio (OR) 4.93, 95% confidence interval (95% CI) 1.61-15.12). The association was detected only in men. The results were supported by a meta-analysis of all published case-control studies comprising a total of 9,152 subjects (chi(2) = 11.37, df = 1, P < 0.001; OR 1.43, 95% CI 1.16-1.78). The present results support the involvement of the DRD2 gene in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 37 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jan 116B: 103-25 |
| PMID | 12497624 |
| Title | D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. |
| Abstract | The D2 dopamine receptor (DRD2) has been one of the most extensively investigated gene in neuropsychiatric disorders. After the first association of the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number of international studies have followed. A meta-analysis of these studies of Caucasians showed a significantly higher DRD2 A1 allelic frequency and prevalence in alcoholics when compared to controls. Variants of the DRD2 gene have also been associated with other addictive disorders including cocaine, nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is a reinforcement or reward gene. The DRD2 gene has also been implicated in schizophrenia, posttraumatic stress disorder, movement disorders and migraine. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress response, personality and treatment outcome characteristics. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the treatment of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 38 | J. Neuroimmunol. 2003 Aug 141: 155-64 |
| PMID | 12965267 |
| Title | Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders. |
| Abstract | There is a hypothesis that autoimmune abnormalities in neurotransmitter receptors might cause some psychiatric disorders. Using a sensitive radioligand assay, we detected serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1, 34.4%), mu-opioid receptor (OPRM1, 13.1%), 5-hydroxytryptamine receptor 1A (HTR1A, 7.4%), and dopamine receptor D2 (DRD2, 4.9%) in 122 psychiatric patients. Positive antibodies to CHRM1 were found in 34.1%, 34.9%, 33.3%, and 9.1% of patients with schizophrenic disorders (n=44), mood disorders (n=63), other psychiatric disorders (n=15) and autoimmune diseases (n=33), respectively. All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to CHRM1, OPRM1, and/or HTR1A. Our data suggest that autoimmunity to neurotransmitter receptors might be associated with the induction of psychiatric symptoms and have some relation to neuroleptic malignant syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 39 | 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 |
| 40 | Pharmacogenomics J. 2003 -1 3: 277-83 |
| PMID | 14583797 |
| Title | Association of dopaminergic and serotonergic genes with tardive dyskinesia in patients with chronic schizophrenia. |
| Abstract | Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 41 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 28-34 |
| PMID | 12707934 |
| Title | Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: association study and meta-analysis. |
| Abstract | An association has been reported between a dopamine D(2) receptor gene (DRD2) Ser311Cys variant and schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 173) and control subjects (n = 236) were assessed for the DRD2 Ser311Cys variant. schizophrenic patients displayed higher Cys311 allele frequencies than control subjects (4.0 vs. 0.8%, chi(2) = 9.49, df = 1, P = 0.002; odds ratio (OR) 4.93, 95% confidence interval (95% CI) 1.61-15.12). The association was detected only in men. The results were supported by a meta-analysis of all published case-control studies comprising a total of 9,152 subjects (chi(2) = 11.37, df = 1, P < 0.001; OR 1.43, 95% CI 1.16-1.78). The present results support the involvement of the DRD2 gene in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 42 | Psychiatr. Genet. 2003 Mar 13: 55-7 |
| PMID | 12605103 |
| Title | Lack of association in Japanese patients between neuroleptic malignant syndrome and the TaqI A polymorphism of the dopamine D2 receptor gene. |
| Abstract | The molecular basis of neuroleptic malignant syndrome (NMS) is unclear, but clinical studies have noted a genetic predisposition. A recent genetic study suggested an association between NMS and the I A polymorphism in the dopamine D2 receptor (DRD2 ) gene. We further examined the association in a larger number of subjects. We studied 49 Japanese patients previously diagnosed with NMS, and 123 schizophrenic patients treated with neuroleptics without occurrence of NMS. PCR and RFLP analyses were performed to screen the I A polymorphism. The I A1 allele frequency was 0.408 in NMS patients and 0.415 in patients without NMS. No significant differences in allelic or genotypic frequencies were observed between the two groups. We cannot conclude that the I A polymorphism is associated with development of NMS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 43 | 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 |
| 44 | Schizophr Bull 2003 -1 29: 169-78 |
| PMID | 12908672 |
| Title | Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? |
| Abstract | The goal of this pilot study was to explore the putative molecular mechanisms underlying the phenotypic discordance of monozygotic (MZ) twins. Thus, patterns of epigenetic DNA modification were investigated in the 5'-regulatory region of the dopamine D2 receptor gene (DRD2) in two pairs of monozygotic twins, one concordant and one discordant for schizophrenia. The bisulfite DNA modification-based approach was used to fine-map methylated cytosines in DRD2 in genomic DNA extracted from lymphocytes. Numerous DNA methylation differences were identified in the analyzed region both within and between the pairs of MZ twins. "Epigenetic distances" between MZ twins were calculated and used for the comparison of twin DRD2 methylation profiles. It was detected that the affected twin from the pair discordant for schizophrenia was epigenetically "closer" to the affected concordant twins than to his unaffected MZ co-twin. Although the epigenetic analysis was conducted for only several hundred base pairs of DRD2, the fact that numerous studies identified nonuniform methylation patterns across the clones of bisulfite-modified DNA from the same individual, as well as nonuniform patterns across different individuals, argues for the universality of intra- and interindividual epigenetic variation. Epigenetic studies should provide insight into the molecular causes of differential susceptibility to a disease in genetically identical organisms that may generalize to singletons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 45 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Apr 20: 98-102 |
| PMID | 12673575 |
| Title | [Pharmacogenetic assessment of antipsychotic-induced tardive dyskinesia: contribution of 5-hydroxytryptamine 2C receptor gene and of a combination of dopamine D3 variant allele (Gly) and MnSOD wild allele (Val)]. |
| Abstract | To further investigate whether the functional polymorphisms of dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes associate with the development of tardive dyskinesia (TD) in schizophrenia, and whether the interactive effects of DRD2, DRD3, 5-hydroxytryptamine 2C receptor (HTR2C) and manganese superoxide dismutase (MnSOD) genes contribute to the severity of TD. The patients with schizophrenia were assessed for TD by the Abnormal Involuntary Movement Scale (AIMS). Eventually, 42 schizophrenics with persistent TD were in the TD group, and 59 schizophrenics without TD were in the non-TD group. The polymorphism of each candidate gene was analyzed using a polymerase chain reaction-based restriction fragment length polymorphism analysis. The genotype distributions of the candidate genes in the groups were all consistent with the Hardy-Weinberg equilibrium. Allele frequencies for -759C/T and -697G/C polymorphisms in HTR2C gene showed a significant excess of -697 variant (P<0.05) in the patients with TD, compared against those in patients without TD. There were no differences in the distributions of the allelic frequencies and genotypes of Taq I. A polymorphism in DRD2 gene, of Ser/Gly polymorphism in DRD3 gene, and of Ala-9Val polymorphism in MnSOD gene between the TD group and non-TD group (P>0.05). Interestingly, as compared with the other joint allelic types, a significant excess of carrying both DRD3 variant allele (Gly) and MnSOD wild allele (Val) was found in the TD group (P<0.05). However, neither the allele and genotypes nor the clinical demographic characteristics contributed to the higher total AIMS scores in the patients of the TD group. There were no significant differences in any of the clinical demographic characteristics between the subgroups of any genotype in TD and non-TD groups. The excess of -697 variant in the promoter regulation region of the HTR2C gene may be a risk factor for the susceptibility to the occurrence of TD in Chinese male patients with schizophrenia. A combination of DRD3 variant allele (Gly) and MnSOD wild allele (Val) may increase the susceptibility to the development of TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 46 | Acta Pharmacol. Sin. 2003 Mar 24: 235-40 |
| PMID | 12617772 |
| Title | No association of antipsychotic agent-induced weight gain with a DA receptor gene polymorphism and therapeutic response. |
| Abstract | To investigate whether there is an association of antipsychotic agent-induced weight gain with the TaqI A polymorphism of dopamine D2 receptor (DRD2) gene and therapeutic response to antipsychotic treatment in schizophrenia. Genotyping was performed using the PCR-RFLP techniques in a total of 117 first-episode Chinese Han schizophrenic patients (mean age 26+/-8 a; 58 male, 59 female). Moreover, the measurements were finished either for baseline weight and body mass index (BMI) or for changed weight and BMI 10 weeks after antipsychotic treatment. The Positive and Negative Symptom Scale (PANSS) was used for the evaluation of the improvement of clinical psychotic symptoms. There was an average increase in body weight of (3+/-3) kg or (6+/-6) % of baseline weight with a changed range of -7 kg - 12 kg or -7.8 % - 32.4 % 10 weeks after treatment, and the change in the BMI was associated with the baseline BMI and patients' age (P=0.0001; P=0.03; respectively). However, there was no significant difference in distribution of allelic frequencies (X2=0.65, v1, P>0.05) and genotype (x2=1.47, v2, P>0.05) between the subgroups, and the change in BMI was not associated with genotypes of DRD2. Furthermore, there was no relationship of the therapeutic response to antipsychotic treatment with changed BMI in the patients (P>0.05). The TaqI A polymorphism of DRD2 gene is therefore unlikely to play an important role in antipsychotic agent-induced weight gain, a side effect of antipsychotic treatment. Furthermore, increase in body weight is unlikely to be prediction of therapeutic response to antipsychotic treatment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 47 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Feb 117B: 57-60 |
| PMID | 12555236 |
| Title | Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. |
| Abstract | Our previous study has suggested that the TaqI A polymorphism of dopamine D2 receptor gene (DRD2) is associated with the predisposition to neuroleptic malignant syndrome (NMS). However, the specificity of this polymorphism as a predictor of NMS dose not seem to be sufficient enough. Meanwhile, it has been shown that the non-carriers of Del allele of the -141C Ins/Del polymorphism in the promoter region of DRD2 have lower dopamine D2 receptor in the brain than the carriers. In addition, dopamine D3 receptor gene has a Ser(9)Gly polymorphism, which may alter the receptor function. The present study examined the association between these three polymorphisms and the development of NMS to investigate if a combination of these polymorphisms could increase the specificity as markers for NMS. The subjects were 17 psychiatric patients who had developed NMS (13 patients with schizophrenia, 3 with major depression, and 1 with dementia of the Alzheimer's type) and 163 schizophrenic patients who had never developed this syndrome. The frequency of the A1 allele was significantly (P = 0.012) higher in the patients who had developed NMS (59%) than in the patients who had not (35%). The proportion of the A1 carriers was significantly (P = 0.003) higher in the patients with NMS (16/17: 94%) than in those without the syndrome (93/163: 57%). However, no significant differences were found in the allele and genotype frequencies of the other two polymorphisms between the two groups. The present study suggests that only the TaqI A polymorphism is at least partly useful as a predictor of NMS, but the -141 C Ins/Del and Ser(9)Gly polymorphisms are not. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 48 | Hum. Mol. Genet. 2003 Feb 12: 205-16 |
| PMID | 12554675 |
| Title | Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. |
| Abstract | Although changes in nucleotide sequence affecting the composition and the structure of proteins are well known, functional changes resulting from nucleotide substitutions cannot always be inferred from simple analysis of DNA sequence. Because a strong synonymous codon usage bias in the human DRD2 gene, suggesting selection on synonymous positions, was revealed by the relative independence of the G+C content of the third codon positions from the isochoric G+C frequencies, we chose to investigate functional effects of the six known naturally occurring synonymous changes (C132T, G423A, T765C, C939T, C957T, and G1101A) in the human DRD2. We report here that some synonymous mutations in the human DRD2 have functional effects and suggest a novel genetic mechanism. 957T, rather than being 'silent', altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed dopamine-induced up-regulation of DRD2 expression. 1101A did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1101A, demonstrating that combinations of synonymous mutations can have functional consequences drastically different from those of each isolated mutation. C957T was found to be in linkage disequilibrium in a European-American population with the -141C Ins/Del and TaqI 'A' variants, which have been reported to be associated with schizophrenia and alcoholism, respectively. These results call into question some assumptions made about synonymous variation in molecular population genetics and gene-mapping studies of diseases with complex inheritance, and indicate that synonymous variation can have effects of potential pathophysiological and pharmacogenetic importance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 49 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jan 116B: 51-4 |
| PMID | 12497614 |
| Title | Polymorphisms of dopamine receptors and tardive dyskinesia among Chinese patients with schizophrenia. |
| Abstract | The putative role of dopamine in the pathophysiology of tardive dyskinesia (TD) makes the genes coding for dopamine receptors the appropriate candidates for study. We investigate the association of the polymorphism of the Ser311Cys and Ser9Gly of the dopamine D2 (DRD2) and D3 receptor (DRD3) genes respectively with TD in Chinese patients with schizophrenia. In a case-control study, 117 Chinese patients with TD were compared to 200 patients without TD. Patients were diagnosed to have schizophrenia according to DSM-IV criteria. Dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS), whereas extrapyramidal side-effects (EPSE) were assessed by the Simpson-Angus Rating Scale. Genotype groups were comparable in age, gender, duration of illness, daily neuroleptic and benzodiazepine dose as well as the mean scores for EPSE. We failed to find an association between the polymorphism of the DRD2 gene with TD but found an increased risk of developing TD among those with D3 serine/serine genotype. Our results did not indicate that the D2 genotype has a role in the pathophysiology of TD in Chinese patients with schizophrenia. The association of TD with the serine/serine genotype of the DRD3 may be an epiphenomenon of patients with a subtype of schizophrenia who had more exposure to neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 50 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Apr 20: 98-102 |
| PMID | 12673575 |
| Title | [Pharmacogenetic assessment of antipsychotic-induced tardive dyskinesia: contribution of 5-hydroxytryptamine 2C receptor gene and of a combination of dopamine D3 variant allele (Gly) and MnSOD wild allele (Val)]. |
| Abstract | To further investigate whether the functional polymorphisms of dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes associate with the development of tardive dyskinesia (TD) in schizophrenia, and whether the interactive effects of DRD2, DRD3, 5-hydroxytryptamine 2C receptor (HTR2C) and manganese superoxide dismutase (MnSOD) genes contribute to the severity of TD. The patients with schizophrenia were assessed for TD by the Abnormal Involuntary Movement Scale (AIMS). Eventually, 42 schizophrenics with persistent TD were in the TD group, and 59 schizophrenics without TD were in the non-TD group. The polymorphism of each candidate gene was analyzed using a polymerase chain reaction-based restriction fragment length polymorphism analysis. The genotype distributions of the candidate genes in the groups were all consistent with the Hardy-Weinberg equilibrium. Allele frequencies for -759C/T and -697G/C polymorphisms in HTR2C gene showed a significant excess of -697 variant (P<0.05) in the patients with TD, compared against those in patients without TD. There were no differences in the distributions of the allelic frequencies and genotypes of Taq I. A polymorphism in DRD2 gene, of Ser/Gly polymorphism in DRD3 gene, and of Ala-9Val polymorphism in MnSOD gene between the TD group and non-TD group (P>0.05). Interestingly, as compared with the other joint allelic types, a significant excess of carrying both DRD3 variant allele (Gly) and MnSOD wild allele (Val) was found in the TD group (P<0.05). However, neither the allele and genotypes nor the clinical demographic characteristics contributed to the higher total AIMS scores in the patients of the TD group. There were no significant differences in any of the clinical demographic characteristics between the subgroups of any genotype in TD and non-TD groups. The excess of -697 variant in the promoter regulation region of the HTR2C gene may be a risk factor for the susceptibility to the occurrence of TD in Chinese male patients with schizophrenia. A combination of DRD3 variant allele (Gly) and MnSOD wild allele (Val) may increase the susceptibility to the development of TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 51 | Acta Pharmacol. Sin. 2003 Mar 24: 235-40 |
| PMID | 12617772 |
| Title | No association of antipsychotic agent-induced weight gain with a DA receptor gene polymorphism and therapeutic response. |
| Abstract | To investigate whether there is an association of antipsychotic agent-induced weight gain with the TaqI A polymorphism of dopamine D2 receptor (DRD2) gene and therapeutic response to antipsychotic treatment in schizophrenia. Genotyping was performed using the PCR-RFLP techniques in a total of 117 first-episode Chinese Han schizophrenic patients (mean age 26+/-8 a; 58 male, 59 female). Moreover, the measurements were finished either for baseline weight and body mass index (BMI) or for changed weight and BMI 10 weeks after antipsychotic treatment. The Positive and Negative Symptom Scale (PANSS) was used for the evaluation of the improvement of clinical psychotic symptoms. There was an average increase in body weight of (3+/-3) kg or (6+/-6) % of baseline weight with a changed range of -7 kg - 12 kg or -7.8 % - 32.4 % 10 weeks after treatment, and the change in the BMI was associated with the baseline BMI and patients' age (P=0.0001; P=0.03; respectively). However, there was no significant difference in distribution of allelic frequencies (X2=0.65, v1, P>0.05) and genotype (x2=1.47, v2, P>0.05) between the subgroups, and the change in BMI was not associated with genotypes of DRD2. Furthermore, there was no relationship of the therapeutic response to antipsychotic treatment with changed BMI in the patients (P>0.05). The TaqI A polymorphism of DRD2 gene is therefore unlikely to play an important role in antipsychotic agent-induced weight gain, a side effect of antipsychotic treatment. Furthermore, increase in body weight is unlikely to be prediction of therapeutic response to antipsychotic treatment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 52 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Feb 117B: 57-60 |
| PMID | 12555236 |
| Title | Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. |
| Abstract | Our previous study has suggested that the TaqI A polymorphism of dopamine D2 receptor gene (DRD2) is associated with the predisposition to neuroleptic malignant syndrome (NMS). However, the specificity of this polymorphism as a predictor of NMS dose not seem to be sufficient enough. Meanwhile, it has been shown that the non-carriers of Del allele of the -141C Ins/Del polymorphism in the promoter region of DRD2 have lower dopamine D2 receptor in the brain than the carriers. In addition, dopamine D3 receptor gene has a Ser(9)Gly polymorphism, which may alter the receptor function. The present study examined the association between these three polymorphisms and the development of NMS to investigate if a combination of these polymorphisms could increase the specificity as markers for NMS. The subjects were 17 psychiatric patients who had developed NMS (13 patients with schizophrenia, 3 with major depression, and 1 with dementia of the Alzheimer's type) and 163 schizophrenic patients who had never developed this syndrome. The frequency of the A1 allele was significantly (P = 0.012) higher in the patients who had developed NMS (59%) than in the patients who had not (35%). The proportion of the A1 carriers was significantly (P = 0.003) higher in the patients with NMS (16/17: 94%) than in those without the syndrome (93/163: 57%). However, no significant differences were found in the allele and genotype frequencies of the other two polymorphisms between the two groups. The present study suggests that only the TaqI A polymorphism is at least partly useful as a predictor of NMS, but the -141 C Ins/Del and Ser(9)Gly polymorphisms are not. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 53 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Apr 118B: 55-9 |
| PMID | 12627467 |
| Title | Gender-specific molecular heterosis and association studies: dopamine D2 receptor gene and smoking. |
| Abstract | If the concept of the gender-specific molecular heterosis is not considered and tested, incorrect conclusions would easily be drawn in association studies. Therein, heterosis and its gender effect in the genetic effect of DRD2 gene for smoking were examined with 187 healthy Korean individuals. The male smokers showed a higher A1 allele frequency (P = 0.016) and prevalence (P = 0.049) than those of the male non-smokers, and the female smokers showed a lower frequency of heterozygotes (P = 0.018) than the female non-smokers. However, the association of DRD2 gene with smoking found in each gender disappeared when both males and females were considered as one group because of the opposite genetic effect of DRD2 gene for smoking: (1) while 75% of heterozygotes males were smokers, only 22% of female heterozygotes were; (2) males showed an excess of heterozygotes and the deviation from Hardy-Weinberg expectations in smokers, while these were true in the female non-smokers; and (3) in non-smokers, females were different from the males exhibiting a significantly higher prevalence (P = 0.005) and frequency (P = 0.015) of A1 allele, and significantly different genotype (P = 0.017) distribution, and higher frequency of heterozygotes (P = 0.055). Meanwhile, in smokers, males showed higher frequency of heterozygotes (P = 0.019) compared to females. The results indicate that gender-specific molecular heterosis at DRD2 gene for smoking is also applicable in healthy individuals as well as schizophrenics. Moreover, this concept has general applicability to other candidate genes and biological phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 54 | Med. Hypotheses 2004 -1 63: 1047-50 |
| PMID | 15504573 |
| Title | Dopamine receptor downregulation: an alternative strategy for schizophrenia treatment. |
| Abstract | schizophrenia is a common and devastating illness. The cause of schizophrenia is still unknown and the simplest formulation of the "Dopamine hypothesis" posits that schizophrenia results from dopaminergic hyperactivity. Under the hypothesis of dopaminergic hyperactivity in schizophrenia, antipsychotics blocking the dopamine D2 receptor (DRD2) and other approaches to reduce dopamine (DA) transmission have been used to treat schizophrenia. I propose that dopamine receptor (DR) downregulation could be an alternative strategy to compromise dopaminergic overactivity implicated in the pathogenesis of schizophrenia. Agonist-induced receptor downregulation includes receptor proteolysis, modulation of receptor gene transcription and affecting of RNA stability. These processes cause a decrease of existing receptors and reduction of receptor synthesis. This hypothesis could explain the antipsychotic mechanisms of DA agonists or partial agonists, like aripiprazole. It is suggested that the development of agents that increase DR downregulation could be an alternative strategy for schizophrenia treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 55 | Int. J. Neuropsychopharmacol. 2004 Dec 7: 489-93 |
| PMID | 15383158 |
| Title | Tardive dyskinesia and DRD2, DRD3, DRD4, 5-HT2A variants in schizophrenia: an association study with repeated assessment. |
| Abstract | We performed an association study between four candidate genes, DRD2, DRD3, DRD4 and 5-HT2A for the presence of tardive dyskinesia (TD) on 84 patients with residual schizophrenia. The sample was evaluated again for the presence of TD after an interval of 3 years. The first group did not exhibit TD in either observation (n=34) while in the second group of patients exhibited TD in at least one of the observations (n=20+18). The clinical and socio-demographic characteristics were not significantly different between the two groups; the genetic analysis revealed a significant correlation between the C/C genotype of 5-HT2A and TD (p=0.017). An association trend was observed between the 'short' variant of DRD4 and TD (p=0.022). We did not observe any significant association for the DRD2 and DRD3 polymorphisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 56 | Pharmacogenomics 2004 Sep 5: 691-8 |
| PMID | 15335289 |
| Title | Pharmacogenetics of dopamine receptors and response to antipsychotic drugs in schizophrenia--an update. |
| Abstract | A considerable number of pharmacogenetic studies have been performed in recent years to define the association of antipsychotic medication response with dopamine receptor polymorphisms and, despite contradictory results, decisive trends have emerged. For the dopamine D2 receptor (DRD2), a trend toward an association with favorable response seems to emerge for the -141C Ins allele of the DRD2 -141C Ins/Del polymorphism and the A1 allele of the Taq1A polymorphism. In the case of the D3 receptor, the Ser9Gly polymorphism has been extensively investigated and a pattern of association is seen between the Ser9 allele and a response to typical antipsychotics, and between the Gly9 allele and a response to atypical antipsychotics. For the D4 receptor, no convincing association results have been reported to date. These trends are discussed with regard to methodological directives and functional implications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 57 | Br J Psychiatry 2004 Aug 185: 147-51 |
| PMID | 15286066 |
| Title | Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele. |
| Abstract | Hyperprolactinaemia induced by D(2) dopamine receptor antagonist antipsychotic medication can result in significant health problems. To examine the role of DRD2 polymorphism on prolactin levels in patients treated with antipsychotic medication. Antipsychotic drugs with different degrees of D(2) receptor binding were given to 144 patients with schizophrenia. Serum prolactin levels were obtained and Taq1A DRD2 alleles were determined. Prolactin levels increased across medication groups reflecting increasingly tight D(2) receptor binding (clozapine, olanzapine, typical antipsychotics and risperidone). In the combined medication group, patients with the DRD2(*)A1allele had 40% higher prolactin levels than patients without this allele. In patients treated with clozapine (the loosest D(2) receptor binding agent), patients with the DRD2(*)A1allele had prolactin levels twice those of patients without this allele. Patients with the DRD2A1 allele receiving antipsychotic medications had higher prolactin levels and were overrepresented among those with hyperprolactinaemia, suggesting greater functional D(2) receptor binding in this group. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 58 | Neurotox Res 2004 -1 6: 51-6 |
| PMID | 15184105 |
| Title | Candidate gene studies of antipsychotic drug efficacy and drug-induced weight gain. |
| Abstract | Converging data suggest that the identification of the molecular variants that influence antipsychotic drug response may soon be feasible. For the most part, these studies have focused on the new atypical antipsychotic agents, particularly clozapine. Although initial data in this regard has been inconclusive, recent studies have suggested that variation in the gene that codes for the dopamine D2 receptor (DRD2) may significantly influence the clinical efficacy of a number of typical and atypical antipsychotic drugs, perhaps via a variant that influences messenger RNA (mRNA) stability and translation. Studies of antipsychotic-induced weight gain have been more consistent than studies of antipsychotic drug efficacy, perhaps because weight dysregulation represents a more powerful phenotype for genetic studies, with a specific single nucleotide polymorphism (SNP) in the 5- hydroxytryptamine 2C (5-HT2c) receptor being associated with weight gain across diverse samples. Larger, more comprehensive studies are needed to confirm these results, but taken together, they suggest that pharmacogenetic strategies may be critical towards gaining a more precise understanding of the mechanism of action of antipsychotic drugs in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 59 | Psychiatry Res 2004 Mar 125: 185-91 |
| PMID | 15051179 |
| Title | Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a Portuguese population. |
| Abstract | schizophrenia is a highly heritable condition, as demonstrated in family, twin and adoption studies. Candidate genes from the dopaminergic system have long been hypothesized to be involved in the etiology of this disorder. In the present study, we investigated the genetic association between polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3) genes and schizophrenia. We examined 90 trios from Portugal, and negative results were obtained from association studies with both Haplotype Relative Risk (HRR) and Transmission Disequilibrium Test (TDT), as well as TRANSMIT. Therefore, we conclude that neither the DRD2 nor the DRD3 gene polymorphisms investigated are associated with schizophrenia in our sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 60 | CNS Spectr 2004 Apr 9: 302-8 |
| PMID | 15048055 |
| Title | Nonparametric linkage analysis between schizophrenia and candidate genes of dopaminergic and serotonergic systems. |
| Abstract | Alterations in dopaminergic and serotonergic systems have been implicated in the pathophysiology of schizophrenia for many years. This study was performed to assess the possible involvement of the dopamine receptor genes D2 (DRD2), D3, D4, serotonin receptor genes 1Da, 1Db, and 2A in the etiology of schizophrenia. We examined 33 multiplex schizophrenic families from Portugal. Linkage analysis performed by GENEHUNTER showed nonsignificant linkage for these genes. A maximum nonparametric linkage score of 1.635 (P=.032) at DRD2 gene was observed, and this finding suggests DRD2 gene for further studies. the polymorphisms studied at dopamine receptor genes D3, D4, serotonin receptor genes 1Da, 1Db, and 2A do not have a major effect in susceptibility to schizophrenia in a Portuguese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 61 | Schizophr. Res. 2004 Mar 67: 75-85 |
| PMID | 14741327 |
| Title | The 3' region of the DRD2 gene is involved in genetic susceptibility to schizophrenia. |
| Abstract | The gene coding for the D2 dopamine receptor (DRD2) is considered as one of the most relevant candidate genes in schizophrenia. Previous genetic studies focusing on this gene yielded conflicting results, for example because of differences in methodology (linkage versus association studies) and variability in the loci analyzed (the DRD2 gene having many polymorphic sites). We used a progressive strategy with two different approaches (case-control and transmission disequilibrium test) and investigated six genetic polymorphisms spanning the DRD2 gene in 103 patients with DSM-IV criteria of schizophrenia, their 206 parents and 83 matched healthy control subjects. We found a significant excess of the A2 allele in subject with schizophrenia compared to unaffected controls. An excess of transmission of the A2 allele (and haplotypes containing this marker) from the parents to the affected children was also observed. Interestingly, the TaqI A1/A2 polymorphism, located 9.5 kb downstream from the DRD2 gene, maps in a novel gene, untitled "X-kinase", and leads to a 713Glu-->Lys substitution in exon 8. As the analysis of the other markers within the DRD2 gene does not improve the strength of the association, our data are in favor of a specific role of the 3' chromosomic region of the DRD2 gene in the vulnerability to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 62 | CNS Spectr 2004 Apr 9: 302-8 |
| PMID | 15048055 |
| Title | Nonparametric linkage analysis between schizophrenia and candidate genes of dopaminergic and serotonergic systems. |
| Abstract | Alterations in dopaminergic and serotonergic systems have been implicated in the pathophysiology of schizophrenia for many years. This study was performed to assess the possible involvement of the dopamine receptor genes D2 (DRD2), D3, D4, serotonin receptor genes 1Da, 1Db, and 2A in the etiology of schizophrenia. We examined 33 multiplex schizophrenic families from Portugal. Linkage analysis performed by GENEHUNTER showed nonsignificant linkage for these genes. A maximum nonparametric linkage score of 1.635 (P=.032) at DRD2 gene was observed, and this finding suggests DRD2 gene for further studies. the polymorphisms studied at dopamine receptor genes D3, D4, serotonin receptor genes 1Da, 1Db, and 2A do not have a major effect in susceptibility to schizophrenia in a Portuguese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 63 | Alcohol. Clin. Exp. Res. 2004 Mar 28: 374-84 |
| PMID | 15084894 |
| Title | Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. |
| Abstract | The role of the dopamine D2 receptor (DRD2) gene in the development of alcohol abuse or dependence is controversial. The controversy is due in part to the disparate definitions pertaining to the control groups used and to the definitions of subtypes in alcohol dependence. In the Han Chinese population, the alcohol dehydrogenase 1B*2/*2 (ADH1B*2/*2) genotype and the aldehyde dehydrogenase 2*2 (ALDH2*2) allele have been considered as protective factors against alcohol abuse or dependence. Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism. We hypothesized that the ADH1B and ALDH2 genes might interact with the DRD2 gene and that the association between the DRD2 gene and alcohol dependence might be affected by different ADH1B and ALDH2 genotypes. This study examined whether the DRD2 gene is associated with specific subtypes of alcohol dependence and evaluated the relationship between the DRD2 gene and alcohol-metabolizing genes in a specific subtype of alcohol dependence. Of the 465 Han Chinese subjects who were recruited for the study, 71 were classified with pure alcohol dependence, 113 with both alcohol dependence and anxiety-depression (ANX/DEP ALC), and 129 with anxiety-depression but without alcohol dependence (ANX/DEP). The remaining 152 subjects were supernormal controls. All subjects were interviewed with the Chinese version of the modified Schedule of Affective Disorders and schizophrenia-Lifetime; all alcohol dependence, anxiety, and major depressive diagnoses were made according to DSM-IV criteria. The DRD2 gene was not found to be associated with pure alcohol dependence or ANX/DEP, but was found to be associated with ANX/DEP ALC. Furthermore, the association between the DRD2 gene and ANX/DEP ALC was shown to be under the control of the ALDH2*1/*1 and ADH1B*1/*2 genotypes. ANX/DEP ALC is a specific subtype of alcohol dependence. Because ANX/DEP ALC was associated with the DRD2 gene only under the stratification of ADH1B*1/*2 or ALDH2*1/*1, the DRD2 gene might interact with the ADH1B gene and the ALDH2 gene, respectively, in the development of ANX/DEP ALC in the Taiwan Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 64 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Feb 125B: 69-78 |
| PMID | 14755448 |
| Title | Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. |
| Abstract | schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 65 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 21-3 |
| PMID | 15211624 |
| Title | DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis. |
| Abstract | The gene DRD2, which codes for dopamine receptor D2, has been considered a prime candidate for allelic association testing with schizophrenia based on the strong evidence for involvement of this protein in disease pathophysiology. Recent meta-analyses confirmed a small but reliable association between schizophrenia and the cysteine-coding allele of the Cys311Ser polymorphism of DRD2. In the present study, we sought to determine if another polymorphism (the -141C insertion/deletion) in the same gene, which has been reported to be associated with schizophrenia in several individual studies, would show a similar pattern of association with the disease in a pooled dataset. The pooled odds ratio for the insertion allele obtained from 10 case-control studies was 1.1, which was not significant (P = 0.580); however, there was marked heterogeneity among the findings of individual studies, suggesting that some underlying factor influenced the size of their observed effects. Yet, neither ethnicity, the age of the control group, nor the gender composition of the samples reliably influenced effect size. Because linkage disequilibrium patterns between various DRD2 polymorphisms are not yet known, it remains possible that divergent meta-analytic findings at both commonly examined mutation sites within DRD2 are accurate. Haplotype analysis within this gene would be useful for definitively specifying the role of this gene in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 66 | Int. J. Neuropsychopharmacol. 2004 Dec 7: 461-70 |
| PMID | 15140279 |
| Title | Effects of dopamine D2 receptor Ser311Cys polymorphism and clinical factors on risperidone efficacy for positive and negative symptoms and social function. |
| Abstract | Risperidone is an atypical antipsychotic agent with efficacy for both positive and negative symptoms of schizophrenia. However, what makes an antipsychotic 'atypical' remains unclear. We recently found that the T102C polymorphism in the 5-HT2A receptor gene could affect risperidone's efficacy for negative symptoms. The present study investigated the effect of the Ser311Cys polymorphism in the dopamine D2 receptor (DRD2) gene on risperidone treatment response. A total of 123 Han Chinese patients with acutely exacerbated schizophrenia were given risperidone for up to 42 days. Clinical manifestations were measured bi-weekly with Positive and Negative Syndrome Scale (PANSS) and Nurses' Observation Scale for Inpatients Evaluation (NOSIE, for assessment of social function). For adjusting the within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was utilized to analyse the effects of Ser311Cys polymorphism and other covariates on clinical performance. Compared with patients who had the Ser311Ser genotype, patients with the Ser311Cys genotype had lower scores on PANSS Positive, Negative, General Psychopathology and Cognitive subscales and NOSIE, after adjustment for 5-HT2A T102C polymorphisms and other confounders. The 5-HT2A T102C polymorphism had marginal influences on PANSS Total and Negative subscale scores. Male gender, fewer previous hospitalizations, and higher risperidone dose predicted better treatment response after control for other variables. The preliminary results suggest that variations in the DRD2 gene influence risperidone treatment response for positive, negative, and cognitive symptoms, general psychopathology, and social functioning. Several clinical factors may also contribute to inter-individual differences in risperidone treatment response. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 67 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 May 127B: 51-9 |
| PMID | 15108180 |
| Title | Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation. |
| Abstract | Fine-tuning of neuronal connections during development is regulated through environmental interactions. Some fine-tuning occurs through changes in gene expression and/or epigenetic gene-specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S-adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short-term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene-specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi-factorial psychiatric disorders. For example, L-methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This gene's protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimer's disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 68 | J Neural Transm (Vienna) 2005 Nov 112: 1575-82 |
| PMID | 15785860 |
| Title | An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia. |
| Abstract | Dopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 69 | Pharmacogenomics 2005 Mar 6: 139-49 |
| PMID | 15882132 |
| Title | Pharmacogenetic studies of response to risperidone and other newer atypical antipsychotics. |
| Abstract | Risperidone and other newer atypical antipsychotics are becoming the mainstay for schizophrenia treatment. Recent studies suggest that the 5-hydroxytryptamine receptor 2A (5-HT2A) gene (HTR2A) T102C and G-1438A polymorphisms may influence treatment response of risperidone or olanzapine for schizophrenia's negative symptoms (e.g., blunted affect and social withdrawal). In addition, the HTR6 T267C polymorphism has been linked to risperidone response for positive symptoms (delusions and hallucinations). The dopamine D2 receptor (DRD2) Ser311Cys polymorphism may also play a role in determining risperidone efficacy for positive, negative and cognitive symptoms, the DRD2 Ins-A2/Del-A1 diplotype may predict better risperidone response, and the DRD3 Ser311Cys variant may affect general treatment response of several atypical agents. Although investigators have started to explore genetic effects on cognitions of schizophrenia patients receiving antipsychotics, future larger sized pharmacogenetic studies on both psychotic symptoms and cognitive functions are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 70 | Neurosci. Lett. 2005 Mar 376: 1-4 |
| PMID | 15694263 |
| Title | Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. |
| Abstract | Previous studies have demonstrated that the -141C Ins/Del and TaqI A polymorphisms in the DRD2 gene affect the density of the dopamine D2 receptor. The present study examines the correlation between these two polymorphisms and the therapeutic response to chlorpromazine, a typical antipsychotic drug, in 135 inpatients with schizophrenia. Clinical symptoms were evaluated using the Brief Psychiatry Rating Scale (BPRS) before and after 8 weeks of treatment with 300-600 mg/day of chlorpromazine. Our results show that genotyping -141C Ins/Del may help to predict the efficacy of chlorpromazine treatment (P=0.01) due to the fact that patients with no Del allele showed greater improvement than those with Del allele on the overall BPRS (P=0.03), and that, therefore, the potential for therapy in patients with schizophrenia is related to the -141C Ins/Del polymorphism in the DRD2 gene. However, no such relationship was found for the TaqI A polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 71 | Schizophr. Res. 2005 Feb 73: 31-7 |
| PMID | 15567074 |
| Title | The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia. |
| Abstract | The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and postmortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 72 | Med. Hypotheses 2005 -1 64: 197-200 |
| PMID | 15533641 |
| Title | Adenosine A2a receptor/dopamine D2 receptor hetero-oligomerization: a hypothesis that may explain behavioral sensitization to psychostimulants and schizophrenia. |
| Abstract | The mechanisms underlying psychostimulant-induced behavioral sensitization and schizophrenia are yet to be fully elucidated. Evidence suggests that the dopamine D2 receptor (DRD2) as well as other neurotransmitter system receptors may be involved in the two conditions, and previous reports have hypothesized that oligomerization of dopamine receptors and analogs from other neurotransmitter systems may underlie the mechanism responsible. This paper describes findings which show co-localization of DRD2 and the adenosine A2a receptor (A2aAR) in the striatum, interaction between the two receptors and A2aAR/DRD2 hetero-oligomerization in the neuronal cell. The possibility that A2aAR/DRD2 hetero-oligomerization may be involved in the development of psychostimulant-induced behavioral sensitization or the pathogenesis of schizophrenia is explored. A2aAR/DRD2 hetero-oligomerization can enhance dopaminergic function, resulting in an increased behavioral response to psychostimulants or the development of psychotic symptoms. Receptor oligomerization can affect receptor degradation, which may affect the persistence of behavioral sensitization or psychotic symptoms. The proposed A2aAR/DRD2 hetero-oligomerization model may suggest new directions in the understanding and treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 73 | J Neural Transm (Vienna) 2005 Nov 112: 1575-82 |
| PMID | 15785860 |
| Title | An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia. |
| Abstract | Dopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 74 | Neurosci. Lett. 2005 Mar 376: 1-4 |
| PMID | 15694263 |
| Title | Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. |
| Abstract | Previous studies have demonstrated that the -141C Ins/Del and TaqI A polymorphisms in the DRD2 gene affect the density of the dopamine D2 receptor. The present study examines the correlation between these two polymorphisms and the therapeutic response to chlorpromazine, a typical antipsychotic drug, in 135 inpatients with schizophrenia. Clinical symptoms were evaluated using the Brief Psychiatry Rating Scale (BPRS) before and after 8 weeks of treatment with 300-600 mg/day of chlorpromazine. Our results show that genotyping -141C Ins/Del may help to predict the efficacy of chlorpromazine treatment (P=0.01) due to the fact that patients with no Del allele showed greater improvement than those with Del allele on the overall BPRS (P=0.03), and that, therefore, the potential for therapy in patients with schizophrenia is related to the -141C Ins/Del polymorphism in the DRD2 gene. However, no such relationship was found for the TaqI A polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 75 | Int J Clin Pharmacol Ther 2005 Apr 43: 163-71 |
| PMID | 15966462 |
| Title | Association between neuroleptic drug-induced extrapyramidal symptoms and dopamine D2-receptor polymorphisms in Japanese schizophrenic patients. |
| Abstract | The aim of the present study is to examine the relationship between dopamine D2-receptor gene (DRD2) polymorphisms (Taq1A, Taq1B, -141C Ins/Del) and the risk of extrapyramidal adverse effects (EPS), assessed according to the Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), or the maintenance dose of antipsychotics in schizophrenic patients. The DIEPSS score was significantly higher in patients bearing the -141C Del allele than in those without it. Taq1A and Taq1B restriction fragment length polymorphisms (RFLPs) did not significantly affect the DIEPSS score. On the other hand, maintenance doses of neuroleptics and antiparkinsonian drugs were significantly higher in patients with the B1 allele of Taq1B RFLP than in those without it, while the Taq1A RFLP and -141C Ins/Del polymorphisms were not significantly related to the maintenance doses. In conclusion, the risk of EPS may be increased in patients with the -141C Del allele of the DRD2 gene. In these patients, antipsychotics should be administered with caution. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 76 | 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 |
| 77 | 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 |
| 78 | Dis. Markers 2005 -1 21: 61-9 |
| PMID | 15920292 |
| Title | Over-expression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers. |
| Abstract | schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL) express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3) was found to be over-expressed in schizophrenic PBL and proposed to be a diagnostic and follow-up marker for schizophrenia. In this study we screened PBL of 13 drug-naive/drug-free schizophrenic patients to identify additional markers of schizophrenia. One of the benefits of our study is the use of blood samples of non-medicated, drug-naive patients. This excludes the possibility that changes detected in gene expression levels might be attributed to the medication rather than to the disorder itself. Among others, genes for dopamine receptor D2 (DRD2) and the inwardly rectifying potassium channel (Kir2.3) were found to be over-expressed in microarray analysis. Increased mRNA levels were confirmed by quantitative real-time PCR (QRT-PCR) using the SybrGreen method and dual labeled TaqMan probes. The use of both molecular markers allows a more rapid and precise prediction of schizophrenia and might help find the optimal medication for schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 79 | Int. J. Neuropsychopharmacol. 2005 Jun 8: 245-53 |
| PMID | 15850500 |
| Title | Association between three functional polymorphisms of the dopamine D2 receptor gene and polydipsia in schizophrenia. |
| Abstract | The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. However, several studies suggest there may be a genetic predisposition to polydipsia, including our previous study demonstrating familial concordance of polydipsia among first-degree relatives with schizophrenia. Antipsychotic medications may contribute to the development of polydipsia and studies show that dopamine D2 receptors are involved in drinking behaviour pathophysiology. Our hypothesis is that polymorphisms in the dopamine D2 receptor gene (DRD2) may confer susceptibility to polydipsia in schizophrenia. We tested for an association between polydipsia in schizophrenia and three functional polymorphisms of DRD2. The three polymorphisms, -141C Ins/Del, Ser311Cys, and TaqIA, were genotyped in patients with polydipsia (n = 64) and in those without polydipsia (n = 91). Of the three polymorphisms, TaqIA was significantly associated with polydipsia [genotype: chi2 = 6.59, df = 2, p = 0.037; allele: chi2 = 6.52, df = 1, p = 0.011, OR 1.81, 95% CI 1.15-2.86]. Haplotype analysis of the three markers found increased significance of the association (global, p = 0.00091). Although based on a relatively small portion of the sample, individual comparison of the common haplotypes showed that haplotype Ins-Cys-A1 was significantly less frequent in patients with polydipsia (p = 0.00082). The present data suggests polymorphisms in DRD2 may confer susceptibility to polydipsia in schizophrenia. To confirm our findings, further studies are warranted on larger samples using more extensive biological measures for diagnosing the polydipsia phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 80 | Curr Psychiatry Rep 2005 Apr 7: 143-51 |
| PMID | 15802092 |
| Title | Meta-analysis in psychiatric genetics. |
| Abstract | The article reviews literature on methods for meta-analysis of genetic linkage and association studies, and summarizes and comments on specific meta-analysis findings for psychiatric disorders. The Genome Scan Meta-Analysis and Multiple Scan Probability methods assess the evidence for linkage across studies. Multiple Scan Probability analysis suggested linkage of two chromosomal regions (13q and 22q) to schizophrenia and bipolar disorder, whereas Genome Scan Meta-Analysis on a larger sample identified at least 10 schizophrenia linkage regions, but none for bipolar disorder. Meta-analyses of pooled ORs support association of schizophrenia to the Ser311Cys polymorphism in DRD2 and the T102C polymorphism in HTR2A, and of attention deficit hyperactivity disorder to the 48-bp repeat in DRD4. The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown. Meta-analyses support linkage of schizophrenia to regions where replicable associations to candidate genes have been identified through positional cloning methods. There are additional supported regions where susceptibility genes are likely to be identified. Linkage meta-analysis has had less clear success for bipolar disorder based on a smaller dataset. Meta-analysis can guide the prioritization of regions for study, but proof of association requires biological confirmation of hypotheses about gene actions. Elucidation of causal mechanisms will require more comprehensive study of sequence variation in candidate genes, better statistical and meta-analytic methods to take all variation into account, and biological strategies for testing etiologic hypotheses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 81 | 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 |
| 82 | 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 |
| 83 | Dis. Markers 2005 -1 21: 61-9 |
| PMID | 15920292 |
| Title | Over-expression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers. |
| Abstract | schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL) express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3) was found to be over-expressed in schizophrenic PBL and proposed to be a diagnostic and follow-up marker for schizophrenia. In this study we screened PBL of 13 drug-naive/drug-free schizophrenic patients to identify additional markers of schizophrenia. One of the benefits of our study is the use of blood samples of non-medicated, drug-naive patients. This excludes the possibility that changes detected in gene expression levels might be attributed to the medication rather than to the disorder itself. Among others, genes for dopamine receptor D2 (DRD2) and the inwardly rectifying potassium channel (Kir2.3) were found to be over-expressed in microarray analysis. Increased mRNA levels were confirmed by quantitative real-time PCR (QRT-PCR) using the SybrGreen method and dual labeled TaqMan probes. The use of both molecular markers allows a more rapid and precise prediction of schizophrenia and might help find the optimal medication for schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 84 | Schizophr. Res. 2006 Sep 86: 323-5 |
| PMID | 16769201 |
| Title | The human dopamine receptor D2 (DRD2) gene is associated with tardive dyskinesia in patients with schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 85 | Acta Psychiatr Scand 2006 Dec 114: 435-8 |
| PMID | 17087792 |
| Title | C957T DRD2 polymorphism is associated with schizophrenia in Spanish patients. |
| Abstract | The objective was to confirm whether a homozygous genotype for the C957 allele of the C957T DRD2 gene single nucleotide polymorphism (SNP) is associated with schizophrenia in an independent study population. We examined the genotypic distribution of this SNP in a set of clinically ascertained schizophrenic patients (n = 131) and age-matched control subjects (n = 364). Individuals were genotyped using automated analysis of fluorescently labeled PCR products. The distribution of grouped genotypes for the C957T DRD2 SNP (CC vs. CT, TT) showed that C homozygote genotype was over-represented in our patient sample when compared with control subjects. This difference reaches the statistical significance (chi(2) = 7.0; df = 1; P = 0.008; OR = 2.05; % CI 1.2-3.4). The findings of this study provide additional evidence that genetic variation at the DRD2 gene plays an important role in the vulnerability to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 86 | Neurosci. Lett. 2006 Oct 407: 195-8 |
| PMID | 16973280 |
| Title | Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia. |
| Abstract | The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5' nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P=0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 87 | Am J Psychiatry 2006 Mar 163: 529-31 |
| PMID | 16513877 |
| Title | DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. |
| Abstract | All antipsychotics act on the dopamine D(2) receptor. The present study extends prior pharmacogenetic investigations of the D(2) receptor gene (DRD2) by examining, in first-episode schizophrenia patients, promoter region variation as a predictor of response time to two first-line atypical antipsychotics. Patients experiencing their first episode of schizophrenia (N=61) were genotyped for two DRD2 promoter region polymorphisms (A-241G and -141C Ins/Del) and were randomly assigned to receive 16 weeks of treatment with either risperidone or olanzapine. Time until sustained response (two consecutive ratings without significant positive symptoms) for rare allele carriers versus wild types was examined by using Kaplan-Meier curves. Relative to wild type homozygotes, G carriers (A-241G) exhibited a significantly faster time until response, whereas -141C Del carriers took a significantly longer time to respond. Diplotype analysis revealed similar results. These findings suggest that variation in the D(2) receptor gene can, in part, explain variation in the timing of clinical response to antipsychotics in patients with first-episode schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 88 | Neurosci. Lett. 2006 Jan 392: 68-71 |
| PMID | 16183199 |
| Title | Association of DRD2 gene variant with schizophrenia. |
| Abstract | schizophrenia is a complex multifactorial disorder for which the pathobiology still remains elusive. Dysfunction of the dopamine D2 receptor signaling has been associated with the illness, but numerous studies provide confounding results. This study investigates the association of synonymous polymorphisms (His313 and Pro319) in the dopamine D2 receptor gene with schizophrenia using a case-control approach, with 101 cases and 145 controls. Our results demonstrated that genotype distribution for the His313 polymorphism was significantly different between schizophrenia patients and control subjects (p=0.0012), while the Pro319 polymorphism did not show any association with the disease. The results suggest that the synonymous SNP His313 in DRD2 may be associated with the illness. However, there is a need for further replication studies with larger sample sets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 89 | Acta Psychiatr Scand 2006 Dec 114: 435-8 |
| PMID | 17087792 |
| Title | C957T DRD2 polymorphism is associated with schizophrenia in Spanish patients. |
| Abstract | The objective was to confirm whether a homozygous genotype for the C957 allele of the C957T DRD2 gene single nucleotide polymorphism (SNP) is associated with schizophrenia in an independent study population. We examined the genotypic distribution of this SNP in a set of clinically ascertained schizophrenic patients (n = 131) and age-matched control subjects (n = 364). Individuals were genotyped using automated analysis of fluorescently labeled PCR products. The distribution of grouped genotypes for the C957T DRD2 SNP (CC vs. CT, TT) showed that C homozygote genotype was over-represented in our patient sample when compared with control subjects. This difference reaches the statistical significance (chi(2) = 7.0; df = 1; P = 0.008; OR = 2.05; % CI 1.2-3.4). The findings of this study provide additional evidence that genetic variation at the DRD2 gene plays an important role in the vulnerability to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 90 | Acta Pharmacol. Sin. 2006 Aug 27: 966-70 |
| PMID | 16867246 |
| Title | Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients. |
| Abstract | Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients. We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 91 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Mar 141B: 149-54 |
| PMID | 16402354 |
| Title | The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. |
| Abstract | Previously we derived independent estimates of the effect of the dopamine D2 receptor (DRD2) Ser311Cys polymorphism on risk for schizophrenia using fixed- and random-effects meta-analyses. Both analyses identified a significant association between the Cys allele and schizophrenia, but neither included all available data. Furthermore, genotype data were not evaluated in either analysis, thus precluding any determination of the mode of inheritance. The present study was conducted to resolve discrepancies between the existing meta-analyses, and provide more comprehensive and accurate estimates of the nature and magnitude of the influence of the Ser311Cys polymorphism on risk for schizophrenia. All discrepancies between the two sets of previously meta-analyzed studies were identified and resolved to the mutual satisfaction of the authors, and the final dataset was analyzed independently by fixed- and random-effects meta-analyses. A total of 27 samples, comprising 3,707 schizophrenia patients and 5,363 control subjects, were included in the analyses of allelic association, while smaller numbers of studies and subjects were included in each of the genotypic association analyses. A significant effect of the Cys allele was observed under both fixed-effects (odds ratio [OR] = 1.4; P = 0.002) and random-effects (OR = 1.4; P = 0.007) models. Cys/Ser heterozygotes were at elevated risk for schizophrenia when compared to Ser/Ser homozygotes (fixed- and random-effects OR = 1.4, p(s) |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 92 | Acta Pharmacol. Sin. 2006 Aug 27: 966-70 |
| PMID | 16867246 |
| Title | Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients. |
| Abstract | Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients. We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 93 | Schizophr. Res. 2007 Dec 97: 302-4 |
| PMID | 17669630 |
| Title | Support for an association of the C939T polymorphism in the human DRD2 gene with tardive dyskinesia in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 94 | Zh Nevrol Psikhiatr Im S S Korsakova 2007 -1 107: 58-60 |
| PMID | 18477981 |
| Title | [The association study of the DRD2 gene C939T polymorphism and schizophrenia.]. |
| Abstract | Physiological evidences and several association studies suggest that the DRD2 gene is implicated in the pathogenesis of schizophrenia. The DRD2 capital ES, Cyrillic939capital TE, Cyrillic (rs6275) single nucleotide polymorphism was genotyped in 272 patients and 362 healthy controls. An association between this polymorphism and schizophrenia was found (p=0,02), the frequency of the TT genotype being higher in patients compared to the controls (c2=7,2; small er, Cyrillic=0,007; OR=1,96, 95% CI=1,2-3,2). The results obtained replicate the data of a previous study of the association between the T allele and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 95 | Behav Brain Funct 2007 -1 3: 65 |
| PMID | 18154681 |
| Title | A lesson not learned: allele misassignment. |
| Abstract | Misassigned alleles can annihilate efforts to control quality in otherwise well-designed genetic association analyses. To date, the issue remains underreported, as is exemplified by studies of a diallelic DRD2 missense variant in schizophrenia. For this variant, allele frequency data have been either misassigned, or incorrectly cited on four consecutive occasions. Contrary to conjecture, low heterozygosity has not guarded against the error with regard to rs1801028, a SNP that features a canonical base pair transversion, G:C. Measures are discussed that may help to identify misassigned alleles, and to avoid related perils pending more systematic investigation of this confounder in genotype-phenotype associations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 96 | 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 |
| 97 | Psychiatr. Genet. 2007 Jun 17: 159-63 |
| PMID | 17417059 |
| Title | A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate. |
| Abstract | Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 98 | Schizophr. Res. 2007 Feb 90: 97-103 |
| PMID | 17207969 |
| Title | The DNA methylation profile within the 5'-regulatory region of DRD2 in discordant sib pairs with schizophrenia. |
| Abstract | Studies of discordance in monozygotic twins have demonstrated that environmental effects play an important role in the pathogenesis of schizophrenia. DNA microarray analysis has revealed upregulation of the DRD2 gene in peripheral blood lymphocytes of schizophrenic patients. We hypothesized that this expression alteration could involve the DNA (CpG) methylation status that is implicated to the transcription status of the gene and in this study we used bisulfited sequence analysis to determine the DNA methylation status of a typical CpGs island within the 5'-regulatory region of DRD2 in peripheral blood lymphocytes from 48 discordant sib pairs suffering from schizophrenia. We found that the methylated cytosines occurred mainly in three clusters. No statistically significant difference in frequency of site-specific cytosine methylation modification of DRD2 between patients and normal controls was found nor did we find any significant association between sex, age on admission or age at onset of schizophrenia and methylated cytosines of DRD2. Our study did not support the hypothesis that site-specific cytosine methylation of DRD2 plays a role in the psychopathology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 99 | Int. J. Neuropsychopharmacol. 2007 Oct 10: 631-7 |
| PMID | 17105675 |
| Title | The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients. |
| Abstract | Antipsychotic drugs exert both therapeutic and adverse effects through dopamine D2 receptor (DRD2) antagonism. Genetic variants of this receptor may be responsible for individual variations in neuroleptic response and may therefore be useful in predicting response. In this study we evaluated the role of six polymorphisms of the DRD2 gene in 125 risperidone-treated Chinese schizophrenia patients following the hypothesis that variation in the DRD2 gene could affect drug response. Response was categorized as a change of >40% on the Brief Psychiatric Rating Scale (BPRS). Our results show that genotyping A-241G may help to predict the efficacy of risperidone treatment on the basis that patients with the A allele showed greater improvement than those with the G allele on the overall BPRS (chi2=7.19, p=0.007, p=0.031 after correction by the program SNPSpD), while other polymorphisms, including -141C Ins/Del, TaqIB, rs1076562, T939C and TaqIA, did not show any association with the response to risperidone. These data suggest that the DRD2 A-241G polymorphism or, alternatively, another genetic variation that is in linkage disequilibrium, may influence response to risperidone in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 100 | J. Theor. Biol. 2007 Feb 244: 463-9 |
| PMID | 17010384 |
| Title | Boolean network analysis of a neurotransmitter signaling pathway. |
| Abstract | A Boolean network is a simple computational model that may provide insight into the overall behavior of genetic networks and is represented by variables with two possible states (on/off), of the individual nodes/genes of the network. In this study, a Boolean network model has been used to simulate a molecular pathway between two neurotransmitter receptor, dopamine and glutamate receptor, systems in order to understand the consequence of using logic gate rules between nodes, which have two possible states (active and inactive). The dynamical properties of this Boolean network model of the biochemical pathway shows that, the pathway is stable and that, deletion/knockout of certain biologically important nodes cause significant perturbation to this network. The analysis clearly shows that in addition to the expected components dopamine and dopamine receptor 2 (DRD2), Ca(2+) ions play a critical role in maintaining stability of the pathway. So this method may be useful for the identification of potential genetic targets, whose loss of function in biochemical pathways may be responsible for disease onset. The molecular pathway considered in this study has been implicated with a complex disorder like schizophrenia, which has a complex multifactorial etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 101 | 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 |
| 102 | J. Neurosci. 2007 Nov 27: 12390-5 |
| PMID | 17989303 |
| Title | Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. |
| Abstract | The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 103 | Psychiatr. Genet. 2007 Jun 17: 159-63 |
| PMID | 17417059 |
| Title | A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate. |
| Abstract | Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 104 | Schizophr. Res. 2007 Feb 90: 97-103 |
| PMID | 17207969 |
| Title | The DNA methylation profile within the 5'-regulatory region of DRD2 in discordant sib pairs with schizophrenia. |
| Abstract | Studies of discordance in monozygotic twins have demonstrated that environmental effects play an important role in the pathogenesis of schizophrenia. DNA microarray analysis has revealed upregulation of the DRD2 gene in peripheral blood lymphocytes of schizophrenic patients. We hypothesized that this expression alteration could involve the DNA (CpG) methylation status that is implicated to the transcription status of the gene and in this study we used bisulfited sequence analysis to determine the DNA methylation status of a typical CpGs island within the 5'-regulatory region of DRD2 in peripheral blood lymphocytes from 48 discordant sib pairs suffering from schizophrenia. We found that the methylated cytosines occurred mainly in three clusters. No statistically significant difference in frequency of site-specific cytosine methylation modification of DRD2 between patients and normal controls was found nor did we find any significant association between sex, age on admission or age at onset of schizophrenia and methylated cytosines of DRD2. Our study did not support the hypothesis that site-specific cytosine methylation of DRD2 plays a role in the psychopathology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 105 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Sep 144B: 809-15 |
| PMID | 17455212 |
| Title | Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment. |
| Abstract | DRD(1) and DRD(2) receptor gene variants have been associated with clinical aspects of schizophrenia; however only specific features were analyzed in different samples. To assess the complex interaction between genetic and clinical factors, we studied the possible cross-interactions between DRD1 and DRD2 dopamine receptor gene polymorphisms, symptomatology of schizophrenia and schizoaffective disorders, and the occurrence of treatment induced side effects taking into consideration possible clinical confounding variables. One hundred thirty one outpatients in stable remission meeting the DSMIV criteria for schizophrenia spectrum disorders and receiving long-term maintenance therapy with haloperidol, fluphenazine, zuclopenthixole, or risperidone were genotyped for DRD1 A-48G, DRD2 Ins-141CDel, and DRD2 Ser311Cys polymorphisms. Psychopathological symptoms were assessed with the positive and negative syndrome scale for schizophrenia (PANSS). Extrapyramidal side effects were assessed with the Simpson-Angus extrapyramidal side effects scale (EPS), the Barnes Akathisia scale (BARS), and the abnormal involuntary movement scale (AIMS). Drug dosage was included as covariant because it was associated with the severity of symptomatology, akathisia, and parkinsonism. No association was observed for DRD1 and DRD2 polymorphisms and extrapyramidal side effects, or with the other clinical variables considered. Our study suggests that DRD1 and DRD2 variants are not liability factors for tardive dyskinesia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 106 | Behav Brain Funct 2007 -1 3: 34 |
| PMID | 17651483 |
| Title | Association of dopamine receptor polymorphisms with schizophrenia and antipsychotic response in a South Indian population. |
| Abstract | Alterations in the dopamine transmission and receptor density are hypothesized in the pathophysiology of schizophrenia but ethnic disparities are reported to exist in disease association and therapeutic response to psychotropic medication. Antipsychotics have higher binding affinity to D2 subtype of dopamine receptor. DRD2 Cys311, TaqIB1 and TaqIA1 variants are considered to have either reduced affinity for dopamine and hypo-dopaminergic activity. We examined the role of Taq1B, Taq1D, S311C, H313H and Taq1A polymorphisms of DRD2 gene in schizophrenia and antipsychotic treatment response in 213 patients and 196 controls from a homogenous South Indian population. A more detailed genotype phenotype association analysis was carried out to understand the disease in terms of its socio-cultural factors. H313HTT genotype was found to be associated with schizophrenia (P = 0.004) while TaqIB1B1 genotype was significantly associated with higher psychopathology score. When treatment response was considered H313HCC, TaqIA2A2 and Taq1D1D1 had higher mean improvement scores. TaqID1D1 and H313HTT genotype were found to be significantly higher in responders than in nonresponder group. Distinct shift in the LD patterns of responder and non-responder group was observed. Certain symptoms were characteristic of our patient population. Following medication the scores and presentation of these symptoms tend to vary in the responder and non-responder groups. Based on genotype phenotype correlations it can be suggested that certain polymorphisms can be defined for their critical functions in disease and their role in treatment response in South Indian population. The present study suggests that in addition to ethnic bias, socio-cultural factors should also be considered while evaluating genotype phenotype correlations, in association and treatment response to complex disorders like schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 107 | J Psychiatry Neurosci 2007 May 32: 185-92 |
| PMID | 17476365 |
| Title | Monoamine oxidase-A polymorphisms might modify the association between the dopamine D2 receptor gene and alcohol dependence. |
| Abstract | Low monoamine oxidase (MAO) activity and the neurotransmitter dopamine are 2 important factors in the development of alcohol dependence. MAO is an important enzyme associated with the metabolism of biogenic amines. Therefore, the present study investigates whether the association between the dopamine D2 receptor (DRD2) gene and alcoholism is affected by different polymorphisms of the MAO type A (MAOA) gene. A total of 427 Han Chinese men in Taiwan (201 control subjects and 226 with alcoholism) were recruited for the study. Of the subjects with alcoholism, 108 had pure alcohol dependence (ALC) and 118 had both alcohol dependence and anxiety, depression or both (ANX/DEP ALC). All subjects were assessed with the Chinese Version of the Modified Schedule of Affective Disorders and schizophrenia-Lifetime. Alcohol dependence, anxiety and major depressive disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. The genetic variant of the DRD2 gene was only associated with the ANX/DEP ALC phenotype, and the genetic variant of the MAOA gene was associated with pure ALC. Subjects carrying the MAOA 3-repeat allele and genotype A1/A1 of the DRD2 were 3.48 times (95% confidence interval = 1.47-8.25) more likely to be ANX/DEP ALC than the subjects carrying the MAOA 3-repeat allele and DRD2 A2/A2 genotype. The MAOA gene may modify the association between the DRD2 gene and ANX/DEP ALC phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 108 | Eur. J. Clin. Pharmacol. 2007 Mar 63: 233-41 |
| PMID | 17225991 |
| Title | Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms. |
| Abstract | Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms (EPS) during treatment with antipsychotic drugs. Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism, tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight dopamine and serotonin receptor and transporter polymorphisms: the Taq1A polymorphism of the dopamine D(2) receptor (DRD2) gene, the Msc1 polymorphism of the dopamine D(3) receptor (DRD3) gene, the variable number of tandem repeat (VNTR) polymorphism of the dopamine transporter (DAT1) gene, four polymorphisms (102T/C, His452Tyr, 516 C/T, and Thr25Asn) of the serotonin 5-HT(2A) receptor (5HTR2A) gene, and the 5HTTLPR polymorphism of the serotonin transporter (5HTT) gene. The frequency of the A1 allele of the DRD2 Taq1A polymorphism was significantly higher in the EPS group than in the control group [16% vs. 7%, P = 0.040; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.7]. Also, the 9 repeat allele of the DAT1 VNTR polymorphism was significantly more common in the EPS group (42% vs. 28%, P = 0.030; OR 1.9; 95% CI 1.1-3.3). Being a carrier of both DRD2 Taq1A A1 and DAT1 VNTR 9 repeat alleles was also significantly associated with the occurrence of EPS (19% vs. 6%, P = 0.040; OR 4.0; 95% CI 1.05-15.2) No significant differences in allele frequencies were found for the other polymorphisms. Presence of the Taq1A A1 allele of the DRD2 and the 9 repeat allele of the DAT1 VNTR polymorphisms might be risk factors for EPS caused by antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 109 | Int. J. Neuropsychopharmacol. 2007 Oct 10: 639-51 |
| PMID | 16959057 |
| Title | Association study of tardive dyskinesia and twelve DRD2 polymorphisms in schizophrenia patients. |
| Abstract | Tardive dyskinesia (TD) is a side-effect of chronic antipsychotic medication. Abnormalities in dopaminergic activity in the nigrostriatal system have been most often suggested to be involved because the agents which cause TD share in common potent antagonism of dopamine D2 receptors (DRD2), that notably is not balanced by effects such as more potent serotonin (5-HT)2A antagonism. Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD. The most consistent findings have been found with the Ser9Gly polymorphism of the DRD3 gene. Although DRD2 has long been hypothesized to be the main target for antipsychotics, only a few polymorphisms in DRD2 have been investigated for their potential involvement in the aetiology of TD. In the present study, we investigated 12 polymorphisms spanning the DRD2 gene and their association with TD in our European Caucasian (n=202) and African-American (n=30) samples. Genotype frequencies for a functional polymorphism, C957T (Duan et al., 2003; Hirvonen et al., 2004), and the adjacent C939T polymorphism were found to be significantly associated with TD (p=0.013 and p=0.022 respectively). DRD2 genotypes were not significantly associated with TD severity as measured by AIMS (Abnormal Involuntary Movement Scale) with the exception of a trend for C939T (p=0.071). Both TD and total AIMS scores were found to be significantly associated with two-marker haplotypes containing C939T and C957T (p=0.021 and p=0.0087 respectively). Preliminary results indicated that C957T was also associated with TD in our African-American sample (p=0.047). Taken together, the present study suggests that DRD2 may be involved in TD in the Caucasian population, although further studies are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 110 | 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 |
| 111 | J. Neurosci. 2007 Nov 27: 12390-5 |
| PMID | 17989303 |
| Title | Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. |
| Abstract | The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 112 | Psychopharmacology (Berl.) 2007 Mar 190: 479-84 |
| PMID | 17102980 |
| Title | Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients. |
| Abstract | Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. To evaluate the impact of polymorphisms in the dopamine D(2) and D(3) and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 113 | Pharmacogenomics 2008 Oct 9: 1437-43 |
| PMID | 18855532 |
| Title | Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. |
| Abstract | Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia. A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale. Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone. These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 114 | Schizophr. Res. 2008 Dec 106: 248-52 |
| PMID | 18838251 |
| Title | Genetic study of eight AKT1 gene polymorphisms and their interaction with DRD2 gene polymorphisms in tardive dyskinesia. |
| Abstract | Tardive dyskinesia (TD) is a motor adverse effect of chronic antipsychotic medication. It has been suggested to involve dopamine neurotransmission system changes. AKT1 acts downstream of the D(2) receptor that is blocked by all antipsychotics to some degree. The AKT1 gene has not been investigated in TD. We examined eight polymorphisms spanning the AKT1 gene and their association with TD in our schizophrenia sample of 193 Caucasians, 76 of which with TD. AKT1 polymorphisms and haplotypes were not significantly associated with TD. However, we detected a significant interaction between rs6275 of DRD2 and rs3730358 of AKT1 (p<1 x 10(-5)). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 115 | Eur. J. Neurol. 2008 Dec 15: 1406-8 |
| PMID | 19049562 |
| Title | The coding-synonymous polymorphism rs1045280 (Ser280Ser) in beta-arrestin 2 (ARRB2) gene is associated with tardive dyskinesia in Chinese patients with schizophrenia. |
| Abstract | Tardive dyskinesia (TD) is a severe and potentially irreversible adverse effect of long-term antipsychotic treatment. Typical antipsychotics are commonly binding to the dopamine receptor D2 (DRD2), but the occurrence of antipsychotic-induced TD is rather delayed; therefore, the development of TD may be associated with mediators or signalling complexes behind DRD2, such as beta-arrestin 2 (ARRB2), an important mediator between DRD2 and serine-threonine protein kinase (AKT) signal cascade. A case-control study to evaluate the association between rs1045280 (Ser280Ser) and antipsychotic-induced TD was performed amongst 381 patients (TD/non-TD = 228/153). There was a significant difference in the genotype distribution between TD and non-TD groups (P = 0.025); furthermore, the allelic analysis indicated that patients with T allele had increased risk of TD occurrence (OR(T) = 1.58, 95% CI = 1.14-2.19, P = 0.007). To the best of our knowledge, this is the first study reporting a positive association between the SNP rs1045280 and TD in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 116 | Pharmacogenomics 2008 Sep 9: 1285-306 |
| PMID | 18781856 |
| Title | Genetic underpinnings of tardive dyskinesia: passing the baton to pharmacogenetics. |
| Abstract | Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 117 | Eur Neuropsychopharmacol 2008 Dec 18: 897-907 |
| PMID | 18786813 |
| Title | Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole. |
| Abstract | We investigated whether the clinical response to aripiprazole differed according to the Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene. In this 26-week, prospective, open-label, double-blind, parallel-group study, 90 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder were recruited and divided into two groups according to their DRD2 genotype (A1A1, n=14; A1A2+A2A2, n=76). The efficacy assessment included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) scores. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BAS). Plasma prolactin levels were also measured. Patients with the A1A1 genotype showed a more favorable therapeutic response to aripiprazole when assessed using the PANSS ratio. The changes in the SAS score from baseline to week 4 also differed according to the genotype group. There were no significant differences in the changes in the CGI, AIMS, and BAS scores or plasma prolactin level between the two genotype groups. The results suggest an association between the DRD2 Taq1A polymorphism status and the variation in the clinical response to aripiprazole. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 118 | J. Clin. Invest. 2008 Jun 118: 2018-21 |
| PMID | 18497888 |
| Title | A signaling pathway AKTing up in schizophrenia. |
| Abstract | The serine/threonine protein kinase AKT (also known as PKB) signaling pathway has been associated with several human diseases, including schizophrenia. Studies in preclinical models have demonstrated that impaired AKT signaling affects neuronal connectivity and neuromodulation and have identified AKT as a key signaling intermediary downstream of dopamine (DA) receptor 2 (DRD2), the best-established target of antipsychotic drugs. A study by Tan et al. in this issue of the JCI strengthens links among AKT signaling, DA transmission, and cognition in healthy individuals and offers potential avenues to explore in an effort to find more effective pharmacotherapies for schizophrenia and related disorders (see the related article beginning on page 2200). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 119 | Psychiatr. Genet. 2008 Jun 18: 122-7 |
| PMID | 18496209 |
| Title | -141C Ins/Del polymorphism of the dopamine D2 receptor gene is associated with schizophrenia in a Spanish population. |
| Abstract | In this study we examined the relationship between dopamine D2 receptor (DRD2) polymorphisms (TaqIA, TaqIB, -141C Ins/Del) and dopamine D3 receptor (DRD3) Ser9Gly polymorphism and the risk of schizophrenia in a Spanish population. Two hundred and forty-three schizophrenia patients and 291 healthy controls from the general population participated in a case-control study. No significant differences were observed in the allele or genotype frequencies of TaqIA, TaqIB or Ser9Gly polymorphisms between the schizophrenia patients and the healthy controls. The frequency of the -141C Del allele was significantly lower in the former group (odds ratio=0.4, P=0.01). The -141C Del allele, which produces lower expression of DRD2, may protect against dopaminergic hyperactivity in schizophrenia. This study is one of the few studies of Caucasian participants that supports the results obtained in the original Japanese study, in which the -141C Ins/Del polymorphism was first described. Furthermore, our findings reinforce the hypothesis that excess dopaminergic activity leads to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 120 | Mov. Disord. 2008 Mar 23: 599-602 |
| PMID | 18175338 |
| Title | The DRD2 TaqIA polymorphism and demand of dopaminergic medication in Parkinson's disease. |
| Abstract | Previous studies have demonstrated that the TaqIA polymorphism of the D2 dopamine receptor gene (DRD2) is associated with response to dopaminergic and antidopaminergic treatment in Parkinson's disease (PD) and schizophrenia, respectively. We tested whether the TaqIA genotype in PD is responsible for demand of dopaminergic medication, measured in total dopaminergic load per year of disease, in a large scale association study based on the gene bank of the German Competence Network on Parkinson's disease. Regression analysis yielded no significant differences between the TaqIA genotypes. We conclude that the DRD2 TaqIA polymorphism alone has no pivotal role for interindividual variability of dopaminergic requirement in PD. We propose a practicable system of measuring dopaminergic treatment for future pharmacogenetic studies in PD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 121 | Synapse 2008 Jan 62: 70-3 |
| PMID | 17960767 |
| Title | Subacute H2O2, but not poly(IC), upregulates dopamine D2 receptors in retinoic acid differentiated SH-SY5Y neuroblastoma. |
| Abstract | Abnormalities of striatal dopaminergic neurotransmission play a significant role in the pathophysiology of central nervous system disorders such as movement disorders, addictions and schizophrenia. The striatum appears to be exposed to intrinsically high levels of oxidative stress (OS). Little is known, however, on the effect of OS on the regulation of the dopamine D2 receptor (DRD2), a key component of striatal dopaminergic neurotransmission. We report here on the effects of H2O2 (a canonical oxidant and non conventional messenger) and polyinosinic-polycytidylic acid (poly(IC) which elicits schizophrenia-like behaviors in newborn rodents and disrupts dopaminergic system development), on DRD2 levels in retinoic acid differentiated SH-SY5Y neuroblastoma. H2O2 elicited a significant increase in DRD2 mRNA and protein levels. Conversely, poly(IC) did not regulate DRD2 levels, although SH-SY5Y cells were confirmed to express TLR3 receptors. Under our conditions, H2O2, but not poly(IC), increased NFkappaB activation (as assessed by p65 nuclear translocation), which paralleled their effects on DRD2 levels regulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 122 | J Psychiatr Res 2008 Jul 42: 639-43 |
| PMID | 17825842 |
| Title | Verification of proposed peripheral biomarkers in mononuclear cells of individuals with schizophrenia. |
| Abstract | Recent studies reported gene expression alterations in peripheral blood cells (PBC) obtained from patients with schizophrenia as compared to healthy controls. These alterations can not only be regarded as potential biomarkers but can also further our understanding of the disease. In light of previous reports, expression levels of the following genes: APOBEC3B, CXCL1, DRD2, GNAO1, Kir2.3, S100A9, and SELENBP1 in PBCs were compared between 30 first-hospitalized patients with schizophrenia and 26 healthy controls using quantitative real-time PCR. A significant elevation (2.6-fold; p<0.05) was confirmed for transcripts from the gene CXCL1 but not from the other genes investigated. Within the patients group, APOBEC3B expression was inversely correlated with duration of neuroleptic treatment. These findings indicate that gene expression in PBC from patients with schizophrenia may not only vary with the methods used for analysis but also with state-related differences in gene expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 123 | 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 |
| 124 | Int. J. Neuropsychopharmacol. 2008 Mar 11: 197-205 |
| PMID | 17681085 |
| Title | Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia. |
| Abstract | Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and beta-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3beta, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among other substrates PKA phosphorylates GSK-3beta. Prolonged DRD2 activation leads to its 'desensitization' which involves GRKs and beta-arrestins. beta-arrestin1 binds to phosphorylated receptors preventing further G-protein stimulation. This study examined whether Par-4, beta-arrestin1, AKT1 and GSK-3beta are involved in the pathophysiology of schizophrenia. Lymphocytes obtained from schizophrenia and bipolar patients and healthy controls recruited from the Beer-Sheva Mental Health Center were transformed by Epstein-Barr virus (EBV) into lymphocyte-derived cell lines (LDCL). Post-mortem brain samples were obtained from the Rebecca L. Cooper Brain Bank, Parkville, Australia. The study was approved by the IRB committees of Beer-Sheva, Israel and Parkville, Australia. Levels of the specific proteins were assayed by Western blotting. beta-arrestin1 protein levels were significantly ~2-fold increased in LDCL from schizophrenia patients while Par-4 protein levels were unaltered. A 63% significant decrease was found in frontal cortex phospho-Ser9-GSK-3beta protein levels in schizophrenia but not in those of AKT1, Par-4 or beta-arrestin1. Elevated beta-arrestin1 protein levels in LDCL and decreased phospho-Ser9-GSK-3beta protein levels in post-mortem frontal cortex of schizophrenia patients vs. control groups support the possible involvement of these proteins in the pathophysiology of schizophrenia. However, since we did not find differences in beta-arrestin1, AKT1 and Par-4 protein levels in post-mortem frontal cortex of schizophrenia patients and although GSK-3beta participates in other signalling cascades we can not rule out the possibility that the differences found reflect deviation in DRD2 signalling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 125 | Ann. N. Y. Acad. Sci. 2008 -1 1129: 200-12 |
| PMID | 18591481 |
| Title | Molecular genetics of attention. |
| Abstract | The sequencing of the human genome and the identification of a vast array of DNA polymorphisms has afforded cognitive scientists with the opportunity to interrogate the genetic basis of cognition with renewed vigor. The extant literature on the molecular genetics of sustained and spatial attention is reviewed herein. Advances in our understanding of the neural substrates of sustained and spatial attention arising from the cognitive neurosciences can help guide putative linkages in cognitive genetics. In line with catecholamine models of sustained attention, associations have been reported between sustained attention and allelic variation in the dopamine beta hydroxylase gene (DBH), the dopamine D2 and D4 receptor genes (DRD2; DRD4) and the dopamine transporter gene (DAT1). Much evidence implicates the cholinergic system in spatial attention. Accordingly, individual differences in spatial attention have been associated with variation in an alpha-4 cholinergic receptor gene (CHRNA4). APOE-epsilon4 allele dosage has been shown to influence the speed of attentional reorienting in independent samples of nonaffected individuals. Preliminary evidence in both healthy children and children with attention deficit hyperactivity disorder (ADHD) suggests and association with variants of the DAT1 gene and the control of spatial attention across the hemifields. With the recent development of high-throughput genotyping techniques, such as microarrays, the time seems ripe for a genomewide association study that can identify quantitative trait loci (QTLs) for sustained and spatial attention. The identification of QTLs for attention will provide a range of novel candidate genes for disorders of attention, such as ADHD and schizophrenia, and will drive cognitive neuroscientists to understand how DNA variation influences the neural substrates of attention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 126 | 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 |
| 127 | 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 |
| 128 | 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 |
| 129 | Pharmacogenet. Genomics 2008 Jul 18: 599-609 |
| PMID | 18551040 |
| Title | Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics. |
| Abstract | This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia. One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia. From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms. Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 130 | Schizophr. Res. 2008 Sep 104: 96-107 |
| PMID | 18715757 |
| Title | Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. |
| Abstract | Genetic association studies on schizophrenia (SZ) have been repeatedly performed over the last two decades, resulting in a consensus that results are generally inconsistent. This consensus has begun to change as a result of meta-analyses (e.g., [Glatt, S.J. and Jonsson, E.G., 2006. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 149-154.]). The schizophreniaGene database (http://www.schizophreniaforum.org/res/sczgene/default.asp) has been a leader in meta-analyses of SZ association data, by dynamically and comprehensively cataloging all public genetic association studies, and preparing meta-analyses of case-control data. There are 19 "top" candidate genes from these analyses (access on December 20, 2007), showing the highest effect sizes and nominally significant associations of at least one variant in the meta-analyses of all ethnic samples or of samples of Caucasian ancestry. We selected 40 polymorphisms in 12 selected "top" genes for additional meta-analyses, which had at least one familial association data. We found gene-wide (correction for the number of meta-analyses for each gene) significant allelic association evidence for seven genes in the combined samples. The odds ratios (ORs) of the associated minor risk alleles range from 1.072 to 1.121, for DRD4, MTHFR, PPP3CC and TP53. For protective allele associations, the ORs are between 0.842 and 0.886, for DAO, IL1B, and SLC6A4. In population-based sub-analyses, we found significant results in four genes in Asians (ORs between 1.084 and 1.309 for DRD4, GABRB2, PPP3CC, and TP53), and one gene in European (OR of 0.888 for SLC6A4). The association of rs1816072 of GABRB2 with SZ in Asians was significant (adjusted P=0.048 after correction for 80 tests). No significant heterogeneity between case-control and family-based study designs was detected in 35 out of 40 polymorphisms. Our results further support eight potential SZ candidate genes and suggest that family data can reasonably be included in the meta-analysis of genetic associations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 131 | Neuropsychobiology 2008 -1 57: 49-54 |
| PMID | 18451638 |
| Title | Association study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia. |
| Abstract | The cause of restless legs syndrome (RLS) is not yet clear, but more promising theories involve dopaminergic deficiency and genetic causes. This study investigated whether single-nucleotide polymorphisms in the genes of dopamine receptors DRD1, DRD2, DRD3 and DRD4 are associated with antipsychotics-induced RLS in schizophrenia. We evaluated 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group and its rating scale for RLS. Genotyping was performed for the DRD1 gene -48A/G, DRD2 gene TaqI A, DRD3 gene Ser9Gly and DRD4 gene -521C/T single-nucleotide polymorphisms. The method of multifactor dimensionality reduction was used to analyze gene-gene interactions. We classified the schizophrenic patients into 96 with and 94 without RLS symptoms. The genotype frequencies of all polymorphisms investigated did not differ significantly between these 2 groups. MDR analysis did not show a significant effect of the 4 dopamine receptor gene variants on susceptibility to antipsychotic-induced RLS symptoms (p > 0.05). These genetics data suggest that the analyzed polymorphisms of the dopamine genes may not be associated with RLS symptoms in schizophrenia. Confirming the results reported here requires a larger-scale study involving patients taking specific antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 132 | Eur. J. Neurol. 2008 Dec 15: 1406-8 |
| PMID | 19049562 |
| Title | The coding-synonymous polymorphism rs1045280 (Ser280Ser) in beta-arrestin 2 (ARRB2) gene is associated with tardive dyskinesia in Chinese patients with schizophrenia. |
| Abstract | Tardive dyskinesia (TD) is a severe and potentially irreversible adverse effect of long-term antipsychotic treatment. Typical antipsychotics are commonly binding to the dopamine receptor D2 (DRD2), but the occurrence of antipsychotic-induced TD is rather delayed; therefore, the development of TD may be associated with mediators or signalling complexes behind DRD2, such as beta-arrestin 2 (ARRB2), an important mediator between DRD2 and serine-threonine protein kinase (AKT) signal cascade. A case-control study to evaluate the association between rs1045280 (Ser280Ser) and antipsychotic-induced TD was performed amongst 381 patients (TD/non-TD = 228/153). There was a significant difference in the genotype distribution between TD and non-TD groups (P = 0.025); furthermore, the allelic analysis indicated that patients with T allele had increased risk of TD occurrence (OR(T) = 1.58, 95% CI = 1.14-2.19, P = 0.007). To the best of our knowledge, this is the first study reporting a positive association between the SNP rs1045280 and TD in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 133 | Arch Iran Med 2008 May 11: 252-6 |
| PMID | 18426314 |
| Title | Linkage and association of DRD2 gene TaqI polymorphism with schizophrenia in an Iranian population. |
| Abstract | D2 dopamine receptor gene has been reported to be one of the most relevant candidate genes in schizophrenia. In this study, we investigated the association between TaqIA and TaqIB dopamine D2 receptor polymorphisms and psychopathology of schizophrenia. The study subjects were 38 acutely exacerbated schizophrenic patients who were all Iranian descent. The control population consisted of 63 healthy individuals with almost the same age as patients and were also of Iranian decent. The TaqIA and TaqIB genotypes, the A1 and A2 alleles, and the B1 and B2 were determined by restriction fragment length polymorphism of the amplified DNA fragments by polymerase chain reaction . For each polymorphism (A or B) the patients were categorized according to their genotype into three groups; i.e. the patients with alleles A1/A1, A1/A2, A2/A2; B1/B1, B1/B2, and B2/B2. No significant association was found between Taq1A or Taq1B gene polymorphisms and schizophrenia in patients compared to the controls. When study subjects were stratified according to their gender, the distribution of the A1/A1 genotype did was significantly different in both men and women (patients vs. controls). Our findings show that there is no genetic association between Taq1A and Taq1B gene polymorphisms and schizophrenia. Further clinical studies should be conducted to confirm and further evaluate these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 134 | Schizophr. Res. 2008 Mar 100: 302-7 |
| PMID | 18255274 |
| Title | Association study of three polymorphisms in the dopamine D2 receptor gene and schizophrenia in the Russian population. |
| Abstract | Polymorphisms in the dopamine D2 receptor gene (DRD2) have repeatedly been associated with schizophrenia. Recently, the C957T polymorphism (rs6277), which alters mRNA stability and dopamine-induced upregulation of DRD2 expression in cell cultures and DRD2 mRNA translation in vitro, was tested for an association with the disease. Frequency of the C allele, corresponding to a normal wild-type level of expression, was higher in patients compared to controls, and that of the T allele was lower. To replicate and extend previous findings, we conducted an association study of the C957T polymorphism and two additional SNPs (C939T and TaqIA) in 311 patients with a DSM-IV diagnosis of schizophrenia and 364 mentally healthy people from the Russian population as controls. The results of our study confirmed the association between the C957T polymorphism and schizophrenia. Consistent with previous findings, frequency of the C allele and the CC genotype were higher in patients compared to the control group (p=0.002). Meta-analysis of total 5 samples also suggests significant allelic association. The distribution of C939T genotypes in the case sample was significantly different from that of the controls: in the case sample, the TT genotype frequency was higher compared to the combined frequency of CT and CC genotypes (p=0.002). Though no association was found between the TaqIA polymorphism and schizophrenia, a haplotype-wise analysis revealed a lower frequency of the T-C (C957T-TaqIA) haplotype in patients (p=0.02). In conclusion, our findings provide additional evidence for an association between the C957T polymorphism and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 135 | 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 |
| 136 | Pharmacogenet. Genomics 2008 Jul 18: 599-609 |
| PMID | 18551040 |
| Title | Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics. |
| Abstract | This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia. One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia. From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms. Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 137 | J Psychiatr Res 2008 Sep 42: 884-93 |
| PMID | 18086475 |
| Title | Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting. |
| Abstract | Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 138 | Neuropsychobiology 2008 -1 57: 49-54 |
| PMID | 18451638 |
| Title | Association study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia. |
| Abstract | The cause of restless legs syndrome (RLS) is not yet clear, but more promising theories involve dopaminergic deficiency and genetic causes. This study investigated whether single-nucleotide polymorphisms in the genes of dopamine receptors DRD1, DRD2, DRD3 and DRD4 are associated with antipsychotics-induced RLS in schizophrenia. We evaluated 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group and its rating scale for RLS. Genotyping was performed for the DRD1 gene -48A/G, DRD2 gene TaqI A, DRD3 gene Ser9Gly and DRD4 gene -521C/T single-nucleotide polymorphisms. The method of multifactor dimensionality reduction was used to analyze gene-gene interactions. We classified the schizophrenic patients into 96 with and 94 without RLS symptoms. The genotype frequencies of all polymorphisms investigated did not differ significantly between these 2 groups. MDR analysis did not show a significant effect of the 4 dopamine receptor gene variants on susceptibility to antipsychotic-induced RLS symptoms (p > 0.05). These genetics data suggest that the analyzed polymorphisms of the dopamine genes may not be associated with RLS symptoms in schizophrenia. Confirming the results reported here requires a larger-scale study involving patients taking specific antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 139 | Arch Iran Med 2008 May 11: 252-6 |
| PMID | 18426314 |
| Title | Linkage and association of DRD2 gene TaqI polymorphism with schizophrenia in an Iranian population. |
| Abstract | D2 dopamine receptor gene has been reported to be one of the most relevant candidate genes in schizophrenia. In this study, we investigated the association between TaqIA and TaqIB dopamine D2 receptor polymorphisms and psychopathology of schizophrenia. The study subjects were 38 acutely exacerbated schizophrenic patients who were all Iranian descent. The control population consisted of 63 healthy individuals with almost the same age as patients and were also of Iranian decent. The TaqIA and TaqIB genotypes, the A1 and A2 alleles, and the B1 and B2 were determined by restriction fragment length polymorphism of the amplified DNA fragments by polymerase chain reaction . For each polymorphism (A or B) the patients were categorized according to their genotype into three groups; i.e. the patients with alleles A1/A1, A1/A2, A2/A2; B1/B1, B1/B2, and B2/B2. No significant association was found between Taq1A or Taq1B gene polymorphisms and schizophrenia in patients compared to the controls. When study subjects were stratified according to their gender, the distribution of the A1/A1 genotype did was significantly different in both men and women (patients vs. controls). Our findings show that there is no genetic association between Taq1A and Taq1B gene polymorphisms and schizophrenia. Further clinical studies should be conducted to confirm and further evaluate these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 140 | 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 |
| 141 | Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 67-70 |
| PMID | 19770837 |
| Title | [The Cys allele of the DRD2 (Ser311Cys polymorphism) is associated with schizophrenia and worse sustained attention in patients]. |
| Abstract | The DRD2 Ser311Cys polymorphism was studied in a sample which included 366 patients with schizophrenia and 387 healthy controls. The frequency of the Cys allele was significantly higher (p<0,009) in the group of patients compared to the controls (8,5% and 3,9%, respectively). Sustained attention assessed by P300 parameters was studied in 66 patients with the SerSer and SerCys genotypes (the CysCys genotype was not observed in the sample studied). A significant effect (p=0,01) of the SerCys genotype on P300 latency in frontal, central and temporal regions was found. Patients with the at-risk allele presented delayed latencies that reflected the lower speed of mental processes related to activation of attention resources. In conclusion, our data support the evidence of association between the Cys allele and schizophrenia obtained earlier for other populations and revealed that carriers of the genotype containing the at-risk allele had delayed P300 latencies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 142 | Arq Neuropsiquiatr 2009 Jun 67: 191-4 |
| PMID | 19547807 |
| Title | Association between the DRD2-141C Insertion/Deletion polymorphism and schizophrenia. |
| Abstract | Epidemiological studies have demonstrated that the genetic component is an important risk factor for the development of schizophrenia. The genes that codify the different compounds of the dopaminergic system have created interest for molecular investigations in patients with schizophrenia because the antipsychotic drugs, especially those of first generation, act on this cerebral system. Thus the aim of the present study was to investigate the possible association between the -141 Ins/Del (rs1799732) polymorphism of the dopamine receptor type 2 (DRD2) and schizophrenia. The distribution of the alleles and genotypes of the studied polymorphism was investigated in a sample of 229 patients and 733 controls. There were statistical differences in the allelic (chi2=9.78; p=0.001) and genotypic genotypic (chi2=12.74; p=0.001) distributions between patients and controls. Thus the -141C Ins/Del polymorphism of the DRD2 gene (allele Ins) was associated to the SCZ phenotype in the investigated sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 143 | Neurotox Res 2009 Jul 16: 50-9 |
| PMID | 19526298 |
| Title | The ANKK1 kinase gene and psychiatric disorders. |
| Abstract | The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22-q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 144 | Neuroscience 2009 Nov 164: 288-99 |
| PMID | 19393294 |
| Title | The genetics of schizophrenia. |
| Abstract | Research on the genetic factors conferring risk for schizophrenia has not provided definitive answers. In the present review, we will discuss potential clinical and genetic limitations intrinsic to the strategies using a diagnostic phenotype. Among clinical factors, uncertainty of the phenotype is certainly a major limitation. Genetic problems include locus heterogeneity and the complex genetic architecture of the phenotype. Given these limiting factors, we will also discuss another hypothesis-driven strategy to uncover genetic risk: the use of quantitative measures (intermediate phenotypes) within more specific neurobiological mechanisms. As a clear example of all these issues and because of the longstanding involvement in the pathophysiology of this disorder, we will review the association of the gene for dopamine D2 receptors (DRD2) with diagnosis of schizophrenia and with specific working memory behavioral and brain activity phenotypes. We conclude by suggesting that hypothesis-free and hypothesis-driven are not mutually exclusive strategies and may provide information at different levels that are both useful and equally valid about genetic risk for a complex diagnostic entity like schizophrenia and for a complex phenotype like psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 145 | Pharmacogenomics J. 2009 Jun 9: 168-74 |
| PMID | 19238168 |
| Title | Association study of tardive dyskinesia and five DRD4 polymorphisms in schizophrenia patients. |
| Abstract | Tardive dyskinesia (TD) is a side effect of chronic antipsychotic medication exposure. Abnormalities in dopaminergic activity in the nigro-striatal system have been most often suggested to be involved because the agents that cause TD share in common potent antagonism of dopamine D(2) receptors (DRD2). Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD, with the most consistent findings being an association between TD and the Ser9Gly polymorphism of the DRD3 gene and the TaqIA site 3' of the DRD2 gene. The DRD4 gene codes for the third member of the D(2)-like dopamine receptor family, and the variable number tandem-repeat polymorphism in exon 3 of DRD4 has been associated with TD. However, other polymorphisms have not been thoroughly examined. In this study, we investigated five polymorphisms spanning the DRD4 gene and their association with TD in our European Caucasian sample (N=171). Although the exon 3 variable number tandem repeat was not associated with TD, haplotypes consisting of four tag polymorphisms were associated with TD in males. This study suggests that DRD4 may be involved in TD in the Caucasian population, although further replication studies are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 146 | J. Hum. Genet. 2009 Feb 54: 98-107 |
| PMID | 19158809 |
| Title | Case-control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population. |
| Abstract | The development of molecular psychiatry in the last few decades identified a number of candidate genes that could be associated with schizophrenia. A great number of studies often result with controversial and non-conclusive outputs. However, it was determined that each of the implicated candidates would independently have a minor effect on the susceptibility to that disease. Herein we report results from our replication study for association using 255 Bulgarian patients with schizophrenia and schizoaffective disorder and 556 Bulgarian healthy controls. We have selected from the literatures 202 single nucleotide polymorphisms (SNPs) in 59 candidate genes, which previously were implicated in disease susceptibility, and we have genotyped them. Of the 183 SNPs successfully genotyped, only 1 SNP, rs6277 (C957T) in the DRD2 gene (P=0.0010, odds ratio=1.76), was considered to be significantly associated with schizophrenia after the replication study using independent sample sets. Our findings support one of the most widely considered hypotheses for schizophrenia etiology, the dopaminergic hypothesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 147 | Depress Anxiety 2009 -1 26: 28-33 |
| PMID | 18833581 |
| Title | The DRD2 gene 957C>T polymorphism is associated with posttraumatic stress disorder in war veterans. |
| Abstract | Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (-141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control individuals without a history of PTSD. No significant association was found between PTSD and the Taq1A or -141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD individuals were more likely to carry the C allele compared to the controls (P=0.021). Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 148 | 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 |
| 149 | Neurotox Res 2009 Jul 16: 50-9 |
| PMID | 19526298 |
| Title | The ANKK1 kinase gene and psychiatric disorders. |
| Abstract | The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22-q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 150 | Psychiatry Investig 2009 Sep 6: 222-5 |
| PMID | 20046399 |
| Title | Genetic polymorphisms in dopamine- and serotonin-related genes and treatment responses to risperidone and perospirone. |
| Abstract | We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 151 | Psychiatr. Genet. 2009 Oct 19: 259-68 |
| PMID | 19512960 |
| Title | Genetic diagnostics of functional variants of the human dopamine D2 receptor gene. |
| Abstract | The importance of dopamine D2 receptors (DRD2) for central nervous dopaminergic signalling makes variants in the DRD2 gene potential modulators of the risk or course of various behavioural, psychiatric or neurologic diseases (e.g. addiction, schizophrenia, Parkinson's disease). We developed Pyrosequencing genetic screening assays for single nucleotide polymorphisms spanning the whole range of the DRD2 gene locus up to the functionally related ankyrin repeat and kinase domain containing 1 gene (ANKK1) located at approximately 10 kb downstream of DRD2. Assays for 11 genetic variants with reported functional association were developed in DNA samples from 300 unrelated healthy Caucasians and validated by independent conventional sequencing. In all DNA samples the DRD2/ANKK1 genetic variants were identified correctly as verified by the control samples. The observed frequencies of homozygous, heterozygous and noncarriers of the minor alleles were in agreement with the Hardy-Weinberg equilibrium. Observed minor allele frequencies were DRD2 rs12364283T>C: 6.5%, rs1799978A>G: 4.8%, rs1799732C del: 14.2%, rs4648317C>T: 12.8%, rs1079597G>A: 13.8%, rs1076560G>T: 14.5%, rs1800496C>T: 0.2%, rs1801028C>G: 3.0%, rs6275C>T: 32.7%, rs6277C>T: 53.0% and ANKK1 rs1800497C>T: 17.5%. The presently developed Pyrosequencing assays are provided to facilitate further research toward personalized approaches to pathophysiological conditions involving behavioural, psychiatric and neurologic disorders including addiction, schizophrenia and Parkinson's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 152 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Apr 33: 470-4 |
| PMID | 19302829 |
| Title | Effects of the DRD3 Ser9Gly polymorphism on aripiprazole efficacy in schizophrenic patients as modified by clinical factors. |
| Abstract | Aripiprazole, a novel antipsychotic agent, has a unique pharmacological action (partial agonist) on the dopamine neurotransmission system. Aripiprazole has high affinity for dopamine D2 and D3 receptors (DRD2 and DRD3). We investigated whether the efficacy of aripiprazole can be predicted by a functional DRD3 gene polymorphism Ser9Gly (rs6280) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n=128) were given aripiprazole for up to four weeks. Patients were genotyped for DRD3 Ser9Gly polymorphism by Restriction Fragment Length Polymorphism (RFLP) method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype and medication dosage were recorded. Psychopathology was measured biweekly with the Positive and Negative Syndrome Scale (PANSS). The effects of genetic and clinical factors on PANSS performance after aripiprazole treatment were analyzed by a mixed model regression approach (SAS Proc MIXED). We found that, although the Ser carriers have numerically larger score reductions when compared with non-carriers in almost all PANSS dimensions, the difference of their effects are statically not significant. However, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype could influence PANSS performance after aripiprazole treatment. This study suggests that DRD3 Ser9Gly polymorphism may not contribute significantly to inter-individual differences in therapeutic efficacy of aripiprazole, but some clinical factors may predict treatment efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 153 | J Psychiatr Res 2009 Mar 43: 600-6 |
| PMID | 18926547 |
| Title | Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients. |
| Abstract | Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 154 | Brain 2009 Feb 132: 417-25 |
| PMID | 18829695 |
| Title | Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. |
| Abstract | Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 155 | Mol. Psychiatry 2009 Sep 14: 885-93 |
| PMID | 18332877 |
| Title | Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan. |
| Abstract | The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior case-control studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous single-nucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a family-based study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps<0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 156 | Psychiatry Investig 2009 Sep 6: 222-5 |
| PMID | 20046399 |
| Title | Genetic polymorphisms in dopamine- and serotonin-related genes and treatment responses to risperidone and perospirone. |
| Abstract | We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 157 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Apr 33: 470-4 |
| PMID | 19302829 |
| Title | Effects of the DRD3 Ser9Gly polymorphism on aripiprazole efficacy in schizophrenic patients as modified by clinical factors. |
| Abstract | Aripiprazole, a novel antipsychotic agent, has a unique pharmacological action (partial agonist) on the dopamine neurotransmission system. Aripiprazole has high affinity for dopamine D2 and D3 receptors (DRD2 and DRD3). We investigated whether the efficacy of aripiprazole can be predicted by a functional DRD3 gene polymorphism Ser9Gly (rs6280) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n=128) were given aripiprazole for up to four weeks. Patients were genotyped for DRD3 Ser9Gly polymorphism by Restriction Fragment Length Polymorphism (RFLP) method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype and medication dosage were recorded. Psychopathology was measured biweekly with the Positive and Negative Syndrome Scale (PANSS). The effects of genetic and clinical factors on PANSS performance after aripiprazole treatment were analyzed by a mixed model regression approach (SAS Proc MIXED). We found that, although the Ser carriers have numerically larger score reductions when compared with non-carriers in almost all PANSS dimensions, the difference of their effects are statically not significant. However, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype could influence PANSS performance after aripiprazole treatment. This study suggests that DRD3 Ser9Gly polymorphism may not contribute significantly to inter-individual differences in therapeutic efficacy of aripiprazole, but some clinical factors may predict treatment efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 158 | J Psychiatr Res 2009 Mar 43: 600-6 |
| PMID | 18926547 |
| Title | Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients. |
| Abstract | Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 159 | Psychiatry Res 2010 May 177: 367-8 |
| PMID | 20388573 |
| Title | A DRD2 polymorphism predicts PANSS score variability in schizophrenia patients treated with antipsychotics. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 160 | J. Neurosci. 2010 Oct 30: 14205-12 |
| PMID | 20962241 |
| Title | Frontostriatal involvement in task switching depends on genetic differences in d2 receptor density. |
| Abstract | Recent studies suggest an association of dopamine D2 receptor (DRD2) availability with flexibility in reward-based learning. We extend these results by demonstrating an association of genetically based differences in DRD2 density with the ability to intentionally switch between nonrewarded tasks: noncarriers of the A1 allele of the DRD2/ANKK1-TaqIa polymorphism, associated with higher DRD2 density, show increased task-switching costs, increased prefrontal switching activity in the inferior frontal junction area, and increased functional connectivity in dorsal frontostriatal circuits, relative to A1 allele carriers. A DRD2 haplotype analysis in the same sample confirmed these results, indicating an association between high D2 density and increased task-switching effort. Our results provide evidence that converges with that from association studies relating increased D2 density to deficits in cognitive flexibility in schizophrenia. We suggest that individual differences in striatal D2 signaling in healthy humans modulate goal-directed gating to prefrontal cortex, thus leading to individual differences in switching intentionally to newly relevant behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 161 | Pharmacogenet. Genomics 2010 Sep 20: 569-72 |
| PMID | 20664489 |
| Title | DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. |
| Abstract | Many antipsychotic medications carry a substantial liability for weight gain, and one mechanism common to all antipsychotics is binding to the dopamine D2 receptor. We therefore examined the relationship between -141C Ins/Del (rs1799732), a functional promoter region polymorphism in DRD2, and antipsychotic-induced weight gain in 58 first episode schizophrenia patients enrolled in a randomized trial of risperidone versus olanzapine. Carriers of the deletion allele (n=29) were compared with Ins/Ins homozygotes (noncarriers, n=29) in a mixed model encompassing 10 weight measurements over 16 weeks. Deletion allele carriers showed significantly more weight gain after 6 weeks of treatment regardless of assigned medication. Although deletion carriers were prescribed higher doses of olanzapine (but not risperidone), dose did not seem to account for the genotype effects on weight gain. Given earlier evidence that deletion carriers show reduced symptom response to medication, additional study of appropriate treatment options for these patients seems warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 162 | Psychiatr. Genet. 2010 Oct 20: 191-8 |
| PMID | 20421849 |
| Title | Habituation in prepulse inhibition is affected by a polymorphism on the NMDA receptor 2B subunit gene (GRIN2B). |
| Abstract | To identify the reliable connectivity between causal genes or variants with an abnormality expressed in a certain endophenotype has been viewed as a crucial step in unraveling the etiology of schizophrenia because of the considerable heterogeneity in this disorder. According to this practical and scientific demand, we aimed to investigate the relationship between seven top-ranked variants in the SZgene database [120-bpTR in DRD4, rs1801028 and rs6277 in DRD2, rs1019385 (T200G) in GRIN2B, rs1800532 in TPH1, rs1801133 (C677T) in MTHFR, rs2619528 (P1765) in DTNBP1] and prepulse inhibition (PPI) and habituation after acoustic stimulus (HAB). Both PPI and HAB were decreased significantly in patients with schizophrenia. In addition, we observed a significant effect of GRIN2B (human NMDA receptor 2B subunit gene, NR2B) genotype on HAB (P<0.05, not corrected). Although these findings need to be replicated in other samples, an underlying mechanism of impaired biological reaction may be influenced by NMDA hypofunctioning in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 163 | Neurosci. Lett. 2010 Jun 477: 53-6 |
| PMID | 19913597 |
| Title | An association study of DRD2 gene polymorphisms with schizophrenia in a Chinese Han population. |
| Abstract | Dopamine signaling is strongly implicated in the etiology of schizophrenia (SZ). Because of the essential role dopamine D2 receptor (DRD2) in dopamine signaling, DRD2 gene has been regarded as one of the top candidate genes for SZ. However, the findings from linkage and association analyses on this gene are mixed and largely inconsistent across various studies. The aim of this study is to investigate the correlation of DRD2 gene variation and the risk for SZ in a Chinese Han population. Three SNPs (rs1801028, rs6275 and rs6277) of DRD2 gene were genotyped in a patient-control sample involving 421 SZ patients and 404 healthy controls. Our data indicated a nominally significant association of rs6277 with SZ, with T-allele being the risk allele (OR=1.58, 95%CI=1.03-2.43, P=0.034). This study suggests that rs6277 T-allele may play a role in the genetic vulnerability for SZ, supporting the involvement of DRD2 gene in SZ pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 164 | Biol. Psychiatry 2010 Oct 68: 657-66 |
| PMID | 20691427 |
| Title | Genetic associations of brain structural networks in schizophrenia: a preliminary study. |
| Abstract | schizophrenia is a complex genetic disorder, with multiple putative risk genes and many reports of reduced cortical gray matter. Identifying the genetic loci contributing to these structural alterations in schizophrenia (and likely also to normal structural gray matter patterns) could aid understanding of schizophrenia's pathophysiology. We used structural parameters as potential intermediate illness markers to investigate genomic factors derived from single nucleotide polymorphism (SNP) arrays. We used research quality structural magnetic resonance imaging (sMRI) scans from European American subjects including 33 healthy control subjects and 18 schizophrenia patients. All subjects were genotyped for 367 SNPs. Linked sMRI and genetic (SNP) components were extracted to reveal relationships between brain structure and SNPs, using parallel independent component analysis, a novel multivariate approach that operates effectively in small sample sizes. We identified an sMRI component that significantly correlated with a genetic component (r = -.536, p < .00005); components also distinguished groups. In the sMRI component, schizophrenia gray matter deficits were in brain regions consistently implicated in previous reports, including frontal and temporal lobes and thalamus (p < .01). These deficits were related to SNPs from 16 genes, several previously associated with schizophrenia risk and/or involved in normal central nervous system development, including AKT, PI3K, SLC6A4, DRD2, CHRM2, and ADORA2A. Despite the small sample size, this novel analysis method identified an sMRI component including brain areas previously reported to be abnormal in schizophrenia and an associated genetic component containing several putative schizophrenia risk genes. Thus, we identified multiple genes potentially underlying specific structural brain abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 165 | J Cogn Neurosci 2010 Sep 22: 1944-54 |
| PMID | 19803686 |
| Title | The association between dopamine DRD2 polymorphisms and working memory capacity is modulated by a functional polymorphism on the nicotinic receptor gene CHRNA4. |
| Abstract | Working memory capacity is extremely limited and individual differences are heritable to a considerable extent. In the search for a better understanding of the exact genetic underpinnings of working memory, most research has focused on functional gene variants involved in the metabolism of the neurotransmitter dopamine. Recently, there has been investigation of genes related to other neurotransmitter systems such as acetylcholine. The potential relevance of a polymorphism located in the gene coding for the alpha4 subunit of the nicotinic acetylcholine receptor (rs#1044396) has been discussed with respect to working memory, but empirical investigations have provided mixed results. However, pharmacological studies in both rodents and humans have shown that the effect of nicotinic agonists on cognitive functions is mediated by dopamine. We therefore hypothesized that such an interaction can be found on a molecular genetic level as well. In order to test this hypothesis, we genotyped 101 healthy subjects for rs#1044396 and three functional polymorphisms on the dopamine d2 receptor gene (rs#1800497, rs#6277, rs#2283265). These subjects performed a visuospatial working memory task in which memory load was systematically varied. We found a significant interaction between rs#1044396 and a haplotype block covering all three dopaminergic polymorphisms on working memory capacity. This effect only became apparent on higher levels of working memory load. This is the first evidence from a molecular genetic perspective that these two neurotransmitter systems interact on cognitive functioning. The results are discussed with regard to their implication for working memory theories and their clinical relevance for treatment of substance abuse and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 166 | Int J Psychiatry Clin Pract 2010 Nov 14: 257-61 |
| PMID | 24917436 |
| Title | Comparison of DRD2 rs1800497 (TaqIA) polymorphism between schizophrenic patients and healthy controls: Lack of association in a Turkish sample. |
| Abstract | Abstract Objective. The association of DRD2 rs1800497 (TaqIA) polymorphisms and schizophrenia has been studied in a number of populations, but the results are contradictory. We aimed to define Taq IA allelic differences between schizophrenic and healthy subjects. Methods. The schizophrenic group consisted of 99 schizophrenic inpatients, diagnosed and treated at Gazi University Hospital Psychiatry Service, the healthy group was composed of 109 subjects who did not suffer from any psychiatric or organic diseases. High molecular weight genomic DNAs were prepared from peripheral venous blood cells by using proteinase K digestion followed by salt extraction method. Target DNA amplification of DRD2 gene (Taq1A, 310-bp region) was performed by polymerase chain reaction (PCR) with the primers 5014 and 971. Results. Of the 208 subjects involved in the study, 98.6% had A1 allele (hetero- or homo-zygote) and 1.4% had A2 allele (homozygote). While all schizophrenia patients had A1 allele, 97.2%, of the healthy subjects (n=106) had A1 allele and there was no significant difference between the groups. Conclusion. This study was the first study related to DRD2 polymorphism conducted in a Turkish schizophrenic patient sample. A great percentage of our sample has A1 allele. Our study could not find a significant association between schizophrenia and DRD2 rs1800497 polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 167 | 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 |
| 168 | J. Pharmacol. Sci. 2010 -1 114: 1-5 |
| PMID | 20716857 |
| Title | Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: Ser311Cys polymorphisms of the dopamine D2-receptor gene and schizophrenia. |
| Abstract | schizophrenia is a debilitating and complex mental disorder with a prevalence of approximately 1% worldwide. The etiology remains unclear, despite massive research efforts. Hyperactive dopaminergic signal transduction in the central nervous system is suggested to be involved in the pathophysiology of schizophrenia (the dopamine hypothesis). The dopamine D(2)-receptor (DRD2) gene is thus a promising candidate for associations with risk of schizophrenia. We investigated DRD2 and found a novel missense nucleotide change causing an amino acid substitution of serine with cysteine at codon 311 (Ser311Cys). We performed an association study using 156 schizophrenia patients and 300 controls. Cys311 in DRD2 was significantly associated with schizophrenia. Patients with the Cys311 allele displayed shorter duration of hospitalization and less severe negative symptoms and were more frequently married compared to patients without this allele, suggesting good response to treatment. We expanded samples to 291 patients with schizophrenia (including 11 postmortem brain samples), 579 controls, and 78 patients with affective disorders in a further case-control study. Cys311 was associated with schizophrenia, particularly in patients without negative symptoms, and bipolar disorder with mood-incongruent psychotic symptoms. Three meta-analyses using over 20 published studies confirmed the association. In vitro studies showed that Cys311-type D(2) receptor impairs dopamine-induced sequestration, which appears to be consistent with the dopamine hypothesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 169 | Pharmacol. Biochem. Behav. 2010 Jul 96: 40-7 |
| PMID | 20416333 |
| Title | Disruption of conditioned reward association by typical and atypical antipsychotics. |
| Abstract | Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward-predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100microg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3-30microg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward-predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward-predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 170 | Pharmacogenet. Genomics 2010 Jun 20: 359-66 |
| PMID | 20375926 |
| Title | Dopamine receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment. |
| Abstract | schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain (BWG), which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the dopamine receptor D2 (DRD2) gene may be associated with body weight change after AAP treatment. The study included 479 schizophrenic patients treated with clozapine (n=239), olanzapine (n=70) or risperidone (n=170) for an average of 48.2+/-27.8 months. BWG was defined as an increase of more than 7% of the baseline body weight during AAP treatment. Thirteen common single nucleotide polymorphisms of the DRD2 gene were chosen as tagging single nucleotide polymorphisms. In single-marker-based analysis, the DRD2 rs4436578-C homozygous genotype was found to be associated with a significantly increased risk of BWG [P=0.001, adjusted odds ratio=3.36 (95% confidence interval=1.62 - 7.00)]. In addition, haplotype analysis further showed that the rs4436578-C-allele-related haplotype was more frequent in those patients with BWG than those without (P=0.01 - 0.00019). Our findings confirm the importance of genetic factors in body weight change induced by long-term AAP treatment in patients with schizophrenia and indicate a role of DRD2 in body weight regulation during long-term AAP treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 171 | Am J Psychiatry 2010 Jul 167: 763-72 |
| PMID | 20194480 |
| Title | D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. |
| Abstract | Several lines of evidence suggest that antipsychotic drug efficacy is mediated by dopamine type 2 (D(2)) receptor blockade. Therefore, it seems plausible that variation in the DRD(2) gene is associated with clinical response to antipsychotic drug treatment. The authors conducted the first meta-analysis to examine the relationship between DRD2 polymorphisms and antipsychotic drug response. A MEDLINE search of articles available up to December 31, 2008, yielded 18 prospective studies examining DRD2 gene variation and antipsychotic response in schizophrenia patients; of which, 10 independent studies met criteria for inclusion. Clinical response to antipsychotic treatment was defined as a 50% reduction of either the Brief Psychiatric Rating Scale total score or Positive and Negative Syndrome Scale total score at approximately 8 weeks of follow-up evaluation. Odds ratio was the primary effect-size measure and computed for each polymorphism in each study. Sufficient data were available for two DRD2 polymorphisms: -141C Ins/Del and Taq1A. Six studies reported results for the -141C Ins/Del polymorphism (total sample size: N=687). The Del allele carrier was significantly associated with poorer antipsychotic drug response relative to the Ins/Ins genotype. Eight studies assessed the Taq1A polymorphism and antipsychotic response (total sample size: N=748). There was no significant difference in the response rate among A1 allele carriers relative to individuals with the A2/A2 genotype or A2 allele carriers relative to individuals with the A1/A1 genotype. The DRD2 genetic variation is associated with clinical response to antipsychotic drug treatment. These data may provide proof-of-principle for pharmacogenetic studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 172 | PLoS ONE 2010 -1 5: e9348 |
| PMID | 20179754 |
| Title | Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance. |
| Abstract | Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 173 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Apr 34: 492-9 |
| PMID | 20138949 |
| Title | A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes. |
| Abstract | The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1. We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case-control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1. Case-control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p=0.01, Odds Ratio=1.5, 95% Confidence Interval=1.1-2.2), and the intergenic rs2242592 (p=2.10(-4), OR=1.8, 95%CI=1.3-2.5). A significant SNP-SNP interaction was also found (p<10(-5), OR=2.0, 95%CI=1.6-2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage. Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 174 | Expert Opin Drug Metab Toxicol 2010 Jan 6: 43-53 |
| PMID | 19929252 |
| Title | Pharmacogenetics of D2 dopamine receptor gene in prolactin-secreting pituitary adenomas. |
| Abstract | Dopamine-agonists are the treatment of choice of prolactin-secreting pituitary adenomas (PRL-omas). Their actions on D2 dopamine receptor (DRD2) and the clinical outcome may be affected by polymorphisms. PRL-omas are well-differentiated endocrine tumors expressing DRD2. The dopamine-agonist cabergoline (CB), normalizes prolactin and reduces tumor size in about 80 - 90% of patients. DRD2 polymorphisms correlate with neuropsychiatric disorders, in particular alcoholism and schizophrenia. This review describes the DRD2 polymorphisms, their functional effects, and their impact on susceptibility and response to dopamine-agonists treatment. Searching PubMed database for pertinent articles we found that some DRD2 polymorphisms, particularly TaqIA, TaqIB and NcoI, are associated with different receptor binding in brain areas. One study carried out in patients with PRL-omas found a correlation between NcoI and TaqIA and resistance to CB. In particular, resistant patients had higher prevalence of NcoI-T allele than the responsive patients, while the commonest haplotype (having TaqIA2 allele) was associated with better response. This review deals with the connection between DRD2 polymorphisms and PRL-oma treatment and suggests hypotheses for further studies. Only one study was carried out to analyze the role of DRD2 polymorphisms in PRLomas response to CB. Further studies, including pituitary and hypothalamus in vivo determination of DRD2 binding according to DRD2 genotypes, investigation of possible post-receptorial mechanisms involved, as well as population studies in collaboration with psychiatrists and neurologists, are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 175 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Feb 34: 26-31 |
| PMID | 19766158 |
| Title | Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: Data from an association study. |
| Abstract | To investigate the association between dopaminergic polymorphisms [DRD2 -141C Ins/Del, DRD3 Ser9Gly, and SLC6A3 VNTR] and schizophrenia. Two hundred and eighty-eight outpatients with schizophrenia (DSM-IV criteria) [mean age (SD)=36.4 (12.4), 60.1% males] and 421 unrelated healthy controls [mean age (SD)=40.6 (11.3), 51.3% males] from a homogeneous Spanish Caucasian population were genotyped using standard methods. There was a significant difference in genotype distribution for the DRD2 -141C Ins/Del polymorphism [(chi(2) (2)=12.35, corrected p=0.012]. The -141C Del allele was more common in patients than in controls [0.19 vs. 0.13; chi(2) (1)=9.14, corrected p=0.018, OR (95% CI)=1.57 (1.17-2.10)]. Genotype and allele distributions for DRD3 Ser9Gly and SLC6A3 VNTR polymorphisms were similar in both groups. However, there was tentative evidence of an interaction effect between DRD3 Ser9Gly and SLC6A3 VNTR [Wald=9.56 (4), p=0.049]. Compared to the SLC6A3 10/10 genotype category, the risk of schizophrenia was halved among those with 9/10 [OR=0.51 (95% CI=0.30-0.89), p=0.017]. This protective effect was only present in combination with DRD3 Ser/Ser genotype because of the significant interaction between 9/10 and both Ser/Gly [OR=2.45 (95% CI=1.16-5.17), p=0.019] and Gly/Gly [OR=3.80 (95% CI=1.24-11.63), p=0.019]. This study provides evidence that a genetic variant in the DRD2 gene and possible interaction between DRD3 and SLC6A3 genes are associated with schizophrenia. These findings warrant examination in replication studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 176 | Int J Psychiatry Clin Pract 2010 Nov 14: 257-61 |
| PMID | 24917436 |
| Title | Comparison of DRD2 rs1800497 (TaqIA) polymorphism between schizophrenic patients and healthy controls: Lack of association in a Turkish sample. |
| Abstract | Abstract Objective. The association of DRD2 rs1800497 (TaqIA) polymorphisms and schizophrenia has been studied in a number of populations, but the results are contradictory. We aimed to define Taq IA allelic differences between schizophrenic and healthy subjects. Methods. The schizophrenic group consisted of 99 schizophrenic inpatients, diagnosed and treated at Gazi University Hospital Psychiatry Service, the healthy group was composed of 109 subjects who did not suffer from any psychiatric or organic diseases. High molecular weight genomic DNAs were prepared from peripheral venous blood cells by using proteinase K digestion followed by salt extraction method. Target DNA amplification of DRD2 gene (Taq1A, 310-bp region) was performed by polymerase chain reaction (PCR) with the primers 5014 and 971. Results. Of the 208 subjects involved in the study, 98.6% had A1 allele (hetero- or homo-zygote) and 1.4% had A2 allele (homozygote). While all schizophrenia patients had A1 allele, 97.2%, of the healthy subjects (n=106) had A1 allele and there was no significant difference between the groups. Conclusion. This study was the first study related to DRD2 polymorphism conducted in a Turkish schizophrenic patient sample. A great percentage of our sample has A1 allele. Our study could not find a significant association between schizophrenia and DRD2 rs1800497 polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 177 | Pharmacogenet. Genomics 2010 Jun 20: 359-66 |
| PMID | 20375926 |
| Title | Dopamine receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment. |
| Abstract | schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain (BWG), which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the dopamine receptor D2 (DRD2) gene may be associated with body weight change after AAP treatment. The study included 479 schizophrenic patients treated with clozapine (n=239), olanzapine (n=70) or risperidone (n=170) for an average of 48.2+/-27.8 months. BWG was defined as an increase of more than 7% of the baseline body weight during AAP treatment. Thirteen common single nucleotide polymorphisms of the DRD2 gene were chosen as tagging single nucleotide polymorphisms. In single-marker-based analysis, the DRD2 rs4436578-C homozygous genotype was found to be associated with a significantly increased risk of BWG [P=0.001, adjusted odds ratio=3.36 (95% confidence interval=1.62 - 7.00)]. In addition, haplotype analysis further showed that the rs4436578-C-allele-related haplotype was more frequent in those patients with BWG than those without (P=0.01 - 0.00019). Our findings confirm the importance of genetic factors in body weight change induced by long-term AAP treatment in patients with schizophrenia and indicate a role of DRD2 in body weight regulation during long-term AAP treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 178 | Malays J Med Sci 2011 Oct 18: 44-57 |
| PMID | 22589672 |
| Title | A Nested Allele-Specific Multiplex Polymerase Chain Reaction Method for the Detection of DRD2 Polymorphisms. |
| Abstract | The dopamine D2 receptor gene (DRD2) plays a role in many diseases such as schizophrenia, Parkinson's disease, and addictive behaviour. Methods currently available for the detection of DRD2 polymorphisms are costly and cannot detect all 8 polymorphisms of our research interest simultaneously (Val96Ala, Leu141Leu, Val154Ile, Pro310Ser, Ser311Cys, TaqI A, A-241G, and -141C Ins/Del). Therefore, we developed a nested multiplex polymerase chain reaction (PCR) for simultaneous detection of these polymorphisms. Genomic DNA was extracted from blood using standardised methods. Primers specific at the 3'-end for the polymorphic sites were designed. A two-step PCR method was developed. In the first PCR, a region from exon 3 to 4, exon 7, the promoter region, and the 3'-region of DRD2 were specifically amplified. The products were subsequently used as templates in the second PCR. Sequencing was performed to validate the test results. Specific bands corresponding to the amplified product of interest were obtained. The method was reproducible and specific when used to genotype patients with schizophrenia. The amplified sequences showed 100% homology to the DRD2 sequence. The method was found to be simple, rapid, specific, and reproducible for the simultaneous detection of the DRD2 polymorphisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 179 | AMIA Annu Symp Proc 2011 -1 2011: 1127-33 |
| PMID | 22195173 |
| Title | Exploring schizophrenia drug-gene interactions through molecular network and pathway modeling. |
| Abstract | In this study, we retrieved 39 schizophrenia-related antipsychotic drugs from the DrugBank database. These drugs had interactions with 142 targets, whose corresponding genes were defined as drug targeted genes. To explore the complexity between these drugs and their related genes in schizophrenia, we constructed a drug-target gene network. These genes were overrepresented in several pathways including: neuroactive ligand-receptor pathways, glutamate metabolism, and glycine metabolism. Through integrating the pathway information into a drug-gene network, we revealed a few bridge genes connected the sub-networks of the drug-gene network: GRIN2A, GRIN3B, GRIN2C, GRIN2B, DRD1, and DRD2. These genes encode ionotropic glutamate receptors belonging to the NMDA receptor family and dopamine receptors. Haloperidol was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug-gene interaction level during the treatment of schizophrenia. This study represents the first systematic investigation of drug-gene interactions in psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 180 | Psychiatry Investig 2011 Mar 8: 49-54 |
| PMID | 21519536 |
| Title | No Evidence for an Association between Dopamine D2 Receptor Polymorphisms and Tardive Dyskinesia in Korean Schizophrenia Patients. |
| Abstract | Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic. Dopaminergic activity in the nigrostriatal system have been proposed to be involved in development of TD and dopamine D2 receptors (DRD2) has been regarded as a candidate gene for TD because the antipsychotics have potent antagonism DRD2. This study was aimed to find the relationship between DRD2 gene and antipsychotic-induced TD. We evaluated whether 5 DRD2 single nucleotide polymorphisms (-141Cins>del/TaqID/NcoI/Ser311Cys/TaqIA) are associated with antipsychotic-induced TD in 263 Korean schizophrenia patients with (n=100) and without TD (n=163) who were matched for antipsychotic drug exposure and other relevant variables. Haplotype analyses were also performed. None of 5 polymorphisms were found to be significantly associated with TD and with TD severity as measured by Abnormal Involuntary Movement Scale. Overall haplotype (-141Cins>del/TaqID/NcoI/Ser311Cys/TaqIA) frequency was also not significantly different between TD and non-TD groups, although one rare haplotype (I-D1-T-G-A1) showed significantly different frequency between TD and non-TD groups (2.7% vs. 8.5%, respectively, p=0.031). The present study does not support that DRD2 gene may be involved in TD in the Korean population, although further studies are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 181 | Proc. Natl. Acad. Sci. U.S.A. 2011 Jan 108: 1158-63 |
| PMID | 21187413 |
| Title | DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. |
| Abstract | The D2/AKT1/GSK-3? signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3? proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3?, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 182 | Mol. Psychiatry 2011 Jan 16: 37-58 |
| PMID | 19935739 |
| Title | Identification of blood biomarkers for psychosis using convergent functional genomics. |
| Abstract | There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as DRD2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 183 | J. Neurosci. 2011 May 31: 7349-56 |
| PMID | 21593319 |
| Title | Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats. |
| Abstract | Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to attention deficit/hyperactivity disorder (ADHD), schizophrenia, obsessive-compulsive disorder, and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition [stop-signal reaction time (SSRT)], psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear. This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions of the dopamine D1 receptor (DRD1) antagonist SCH 23390 or dopamine D2 receptor (DRD2) antagonist sulpiride into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC). DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 184 | Neuropsychopharmacology 2011 Jun 36: 1385-96 |
| PMID | 21412225 |
| Title | Dopamine receptor mediation of the exploratory/hyperactivity effects of modafinil. |
| Abstract | Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear. Receptor knockout (KO) mice offer an opportunity to identify receptors that contribute to a drug-induced effect. Here we examined the effects of modafinil on exploration in C57BL/6J mice, in dopamine drd1, DRD2, drd3, and drd4 wild-type (WT), heterozygous (HT), and KO mice, and in 129/SJ mice pretreated with the drd1 antagonist SCH23390 using a cross-species test paradigm based on the behavioral pattern monitor. Modafinil increased activity, specific exploration (rearing), and the smoothness of locomotor paths (reduced spatial d) in C57BL/6J and 129/SJ mice (increased holepoking was also observed in these mice). These behavioral profiles are similar to that produced by the dopamine transporter inhibitor GBR12909. Modafinil was ineffective at increasing activity in male drd1 KOs, rearing in female drd1 KOs, or reducing spatial d in all drd1 KOs, but produced similar effects in drd1 WT and HT mice as in C57BL/6J mice. Neither dopamine DRD2 nor drd3 mutants attenuated modafinil-induced effects. Drd4 mutants exhibited a genotype dose-dependent attenuation of modafinil-induced increases in specific exploration. Furthermore, the drd1 KO effects were largely supported by the SCH23390 study. Thus, the dopamine drd1 receptor appears to exert a primary role in modafinil-induced effects on spontaneous exploration, whereas the dopamine drd4 receptor appears to be important for specific exploration. The modafinil-induced alterations in exploratory behavior may reflect increased synaptic dopamine and secondary actions mediated by dopamine drd1 and drd4 receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 185 | Eur. J. Clin. Pharmacol. 2011 Apr 67: 383-8 |
| PMID | 21181138 |
| Title | Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia. |
| Abstract | Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS?=0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 186 | Exp. Mol. Med. 2011 Jan 43: 44-52 |
| PMID | 21178390 |
| Title | Associations between DRDs and schizophrenia in a Korean population: multi-stage association analyses. |
| Abstract | The dysregulation of the dopaminergic system has been implicated in the pathophysiology of major psychosis, including schizophrenia, with dopamine receptor genes (DRDs) presently targeted as the most promising candidate genes. We investigated DRD1-5 for association with schizophrenia using a multi-stage approach in a Korean sample. One hundred forty-two SNPs in DRD1-5 were selected from the dbSNP, and the associations of each SNP were then screened and typed by MALDI-TOF mass spectrometry using pooled DNA samples from 150 patients with major psychosis and 150 controls. Each of the suggested SNPs was then genotyped and tested for an association within the individual samples comprising each pool. Finally, the positively associated SNPs were genotyped in an extended sample of 270 patients with schizophrenia and 350 controls. Among the 142 SNPs, 88 (62%) SNPs in our Korean population were polymorphic. At the pooling stage, 10 SNPs (DRD1: 2, DRD2: 3, and DRD4: 5) were identified (P<0.05). SNPs rs1799914 of DRD1 (P=0.046) and rs752306 of DRD4 (P=0.017) had significantly different allele frequencies in the individually genotyped samples comprising the pool. In the final stage, with the extended sample, the suggestive association of DRD4 with rs752306 was lost, but the association of DRD1 with rs1799914 gained greater significance (P=0.017). In these large-scale multi-stage analyses, we were able to find a possible association between DRD1 and schizophrenia. These findings suggested the potential contribution of a multi-step strategy for finding genes related to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 187 | Neuropathol. Appl. Neurobiol. 2011 Feb 37: 206-19 |
| PMID | 20874815 |
| Title | Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder. |
| Abstract | signalling through dopamine receptors is of critical importance in the brain and is implicated in schizophrenia and bipolar disorder, but its underlying molecular mechanisms remain poorly understood. using a yeast two-hybrid approach, we previously identified 11 novel dopamine receptor-interacting proteins. Here we compare gene expression levels for 17 genes [including all 11 dopamine receptor interacting proteins, all 5 dopamine receptors (DRD1-DRD5) and DARPP-32] by real-time polymerase chain reaction, using prefrontal cortex post mortem brain samples from 33 schizophrenic, 32 bipolar disorder and 34 control subjects. the expression of C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 genes was altered in schizophrenia and/or bipolar disorder samples relative to controls (P < 0.05). Hierarchical clustering analysis revealed the expression of these five genes (C14ORF28, GNB2L1, MLLT3, DARPP-32, DRD2) is closely correlated in patients. However, in controls, DRD2 expression in relation to the other genes appears to be very different, suggesting abnormal DRD2 activity is an important trigger in the pathophysiology of schizophrenia and bipolar disorder. our data suggest: (i) C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 are important in the pathogenesis of schizophrenia and bipolar disorder; (ii) these two disorders share common disease-related mechanisms linked to dopamine signalling; (iii) the expression of these genes is closely correlated; and (iv) DRD2 provides the initial trigger in the pathogenesis of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 188 | Behav Brain Funct 2011 -1 7: 43 |
| PMID | 21981786 |
| Title | The genetic validation of heterogeneity in schizophrenia. |
| Abstract | schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors. No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39). The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 189 | J Clin Psychopharmacol 2011 Oct 31: 633-7 |
| PMID | 21869689 |
| Title | Comparing the influence of dopamine D? polymorphisms and plasma drug concentrations on the clinical response to risperidone. |
| Abstract | Although several studies have reported that dopamine D? receptor (DRD2) polymorphisms affect the therapeutic efficacy of antipsychotics, other studies have suggested that the plasma drug concentration is related to the clinical response. Currently, there are no definitive data regarding which factor has greater clinical significance. Sixty patients with acute exacerbations of schizophrenia received 6 mg/d of risperidone for 4 weeks. Clinical evaluations using the Brief Psychiatric Rating Scale and the Udvalg for Klinicke Undersøgelser Side Effect Rating Scale were performed before and after administration of risperidone. TaqI A and -141C Ins/Del polymorphisms were determined, and the plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. The TaqI A polymorphism had no effect on therapeutic efficacy, but the -141C Ins/Del polymorphism was associated with an improvement in positive symptoms. In addition, the plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) correlated with the improvement in the total Brief Psychiatric Rating Scale score as well as with positive symptoms. Although there were no associations between DRD2 polymorphisms and psychic adverse effects, the plasma drug concentration was associated with psychic adverse effects. These findings suggest that DRD2 polymorphisms are associated with the therapeutic effects of risperidone as they relate to positive symptoms and that plasma drug concentrations are associated with overall symptoms as well as excitement and cognitive symptoms. Both the genotyping of DRD2 and the monitoring of plasma drug concentrations may be useful for improving clinically dominant symptoms. Further work involving replication in a larger sample is required to support our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 190 | Pharmacogenomics 2011 Aug 12: 1127-36 |
| PMID | 21749219 |
| Title | Sexual dysfunction in male schizophrenia: influence of antipsychotic drugs, prolactin and polymorphisms of the dopamine D2 receptor genes. |
| Abstract | Sexual dysfunction induced by antipsychotic drug treatment is under investigated and under reported. This study aimed to determine the influence of genetic polymorphisms in the D2 dopamine receptor (DRD2) and endothelial nitric oxide synthase (eNOS) genes, and the possible role of blood prolactin concentrations on sexual function in schizophrenic patients. Male remitted schizophrenic patients (n = 100), who were living with a sexual partner and receiving antipsychotic drug monotherapy for at least 6 months, were assessed for sexual and erectile dysfunction using the Arizona Sexual Experience Scale and the five-item version of the International Index of Erectile Function. Blood samples were taken for plasma prolactin determination and genotyped for four polymorphisms: DRD2 (-141C Ins/Del and Taq1A) and eNOS gene (G894T and T-786C). The -141C Ins/Del, but not Taq1A, polymorphism of the DRD2 gene was significantly associated with sexual dysfunction with the del allele being less frequent in sexual dysfunction subjects. Neither of the eNOS polymorphisms, G894T or T-786C, was significantly associated with sexual or erectile dysfunction. Prolactin concentrations were significantly higher in patients with erectile dysfunction but did not reach significance in those with sexual dysfunction. Prolactin was also reduced in -141C Del allele carriers. The frequency and severity of sexual dysfunction in the patients receiving typical antipsychotics was significantly greater than those receiving risperidone or clozapine, while prolactin concentrations were significantly higher in subjects receiving risperidone compared with those receiving clozapine or typical antipsychotics. This is the first evidence indicating that antipsychotic drug treatment in men is associated with a variant in the DRD2 gene in which the -141C Del allele might be a protective factor. While this may, in part, be mediated by effects on prolactin, other factors are likely to contribute to the greater sexual dysfunction in patients receiving typical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 191 | Psychiatr. Genet. 2011 Aug 21: 183-9 |
| PMID | 21206399 |
| Title | Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia. |
| Abstract | Variations in the gene for dopamine D2 receptor (DRD2) might have an influence on the outcome of antipsychotic treatment in schizophrenia. The objective of this study was to investigate the influence of DRD2 polymorphisms on treatment outcomes in patients with schizophrenia. The sample composed of 156 Malaysian outpatients with stable schizophrenia on maintenance antipsychotic treatment at a psychiatric clinic. Psychopathology was evaluated using the Positive and Negative Symptoms Scale. DNA was extracted from blood and subjected to DRD2 PCR-genotyping. Patients with Cys311 allele had more pronounced or severe symptoms of schizophrenia than those without this allele. The former group had a significantly worse treatment response and presented with more prominent negative symptoms. Although there was no significant association between Positive and Negative Symptoms Scale scores and the Pro310Ser, -141C Ins/Del, A-241G or TaqI A polymorphisms, patients with the wild-type -141C Ins allele tended to have less pronounced or milder symptoms of schizophrenia compared with patients with the variant -141C Del allele. The results suggest that DRD2 polymorphisms may have implications for the symptoms of schizophrenia and a predictor for treatment outcomes in a subgroup of patients with schizophrenia in Malaysia. However, further investigation with a larger sample is required to confirm these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 192 | Neuropsychopharmacology 2011 Feb 36: 616-26 |
| PMID | 21107309 |
| Title | Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. |
| Abstract | Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 10(-8), q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 10(-7), q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 10(-7), q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 193 | Synapse 2011 Apr 65: 321-31 |
| PMID | 20730801 |
| Title | Antipsychotic-induced DRD2 upregulation and its prevention by ?-lipoic acid in SH-SY5Y neuroblastoma cells. |
| Abstract | Most antipsychotic (AP) drugs are dopamine (DA) D2 receptor (DRD2) antagonists and remain the main pharmacological treatment of schizophrenia. Long-term AP use can give rise to tardive dyskinesia. It has been reported that chronic treatment with APs induces DRD2 upregulation and oxidative stress, which have been associated with tardive dyskinesia. We showed previously that H?O?-induced oxidative stress increased DRD2 expression in human SH-SY5Y neuroblastoma cells. We report here the effects of AP drugs on DRD2 expression levels in the same cell line and the effects of the inhibition of oxidative phenomena by (±)-?-lipoic acid treatment. Haloperidol, a first-generation AP, induced an increase in DRD2 protein and mRNA levels, whereas amisulpride, a second-generation AP, had no significant effect. (±)-?-Lipoic acid pretreatment reversed the haloperidol-induced DRD2 upregulation in mRNA and protein levels. Furthermore, haloperidol induced a larger increase of oxidative stress biomarkers (protein carbonylation, lipid peroxidation, and superoxide anion production) than amisulpride. (±)-?-Lipoic acid also attenuated AP-induced oxidative stress. Inhibition of catecholamine synthesis by ?-methyl-DL-tyrosine (AMPT) increased DRD2 expression and prevented further increase by APs. Our results suggest that haloperidol-induced DRD2 upregulation is linked to oxidative stress and provide potential mechanisms by which (±)-?-lipoic acid can be considered as a therapeutic agent to prevent and treat side effects related to the use of first-generation APs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 194 | Mol. Biol. Rep. 2011 Feb 38: 1407-11 |
| PMID | 20665240 |
| Title | Dopamine D2 receptor gene -141C Insertion/Deletion polymorphism in Turkish schizophrenic patients. |
| Abstract | schizophrenia is a chronic and neuropsychiatric disease that affects about 0.5-1% of the world's population. An increase in dopamine and dopamine D2 receptor (DRD2) gene products has been well described in schizophrenic patients. Several groups have studied the relationship between dopaminergic hyperactivity and cellular communications have obtained discordant results. Studies searching for the relationship between the schizophrenia and DRD2 gene have gained more interest. Our objective was to determine the relationships among schizophrenic symptoms in schizophrenia subtypes and severity of symptoms in terms of DRD2 gene -141C Insertion/Deletion [Ins/Del; I/D] polymorphism by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) assay method. Genomic DNA was prepared from peripheral blood by using salt extraction method. After amplification of genomic DNA, PCR products were digested with BstNI restriction enzyme for the detection of DRD2 gene -141C Ins/Del polymorphism in 73 schizophrenic patients and 60 healthy control subjects. The allelic frequencies of the DRD2 gene -141C Ins/Del polymorphism in case and control groups were 79.5 and 77.5% for I allele; 20.5 and 22.5% for D allele respectively. There was no significant difference in frequencies of genotypes and alleles between the two groups. In schizophrenic and control subjects, there were no significant relationship in severity of the disease and schizophrenia types among the -141C Ins/Del genotypes and alleles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 195 | Pharmacogenomics 2011 Aug 12: 1127-36 |
| PMID | 21749219 |
| Title | Sexual dysfunction in male schizophrenia: influence of antipsychotic drugs, prolactin and polymorphisms of the dopamine D2 receptor genes. |
| Abstract | Sexual dysfunction induced by antipsychotic drug treatment is under investigated and under reported. This study aimed to determine the influence of genetic polymorphisms in the D2 dopamine receptor (DRD2) and endothelial nitric oxide synthase (eNOS) genes, and the possible role of blood prolactin concentrations on sexual function in schizophrenic patients. Male remitted schizophrenic patients (n = 100), who were living with a sexual partner and receiving antipsychotic drug monotherapy for at least 6 months, were assessed for sexual and erectile dysfunction using the Arizona Sexual Experience Scale and the five-item version of the International Index of Erectile Function. Blood samples were taken for plasma prolactin determination and genotyped for four polymorphisms: DRD2 (-141C Ins/Del and Taq1A) and eNOS gene (G894T and T-786C). The -141C Ins/Del, but not Taq1A, polymorphism of the DRD2 gene was significantly associated with sexual dysfunction with the del allele being less frequent in sexual dysfunction subjects. Neither of the eNOS polymorphisms, G894T or T-786C, was significantly associated with sexual or erectile dysfunction. Prolactin concentrations were significantly higher in patients with erectile dysfunction but did not reach significance in those with sexual dysfunction. Prolactin was also reduced in -141C Del allele carriers. The frequency and severity of sexual dysfunction in the patients receiving typical antipsychotics was significantly greater than those receiving risperidone or clozapine, while prolactin concentrations were significantly higher in subjects receiving risperidone compared with those receiving clozapine or typical antipsychotics. This is the first evidence indicating that antipsychotic drug treatment in men is associated with a variant in the DRD2 gene in which the -141C Del allele might be a protective factor. While this may, in part, be mediated by effects on prolactin, other factors are likely to contribute to the greater sexual dysfunction in patients receiving typical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 196 | Eur. J. Clin. Pharmacol. 2011 Apr 67: 383-8 |
| PMID | 21181138 |
| Title | Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia. |
| Abstract | Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS?=0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 197 | Neuropathol. Appl. Neurobiol. 2011 Feb 37: 206-19 |
| PMID | 20874815 |
| Title | Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder. |
| Abstract | signalling through dopamine receptors is of critical importance in the brain and is implicated in schizophrenia and bipolar disorder, but its underlying molecular mechanisms remain poorly understood. using a yeast two-hybrid approach, we previously identified 11 novel dopamine receptor-interacting proteins. Here we compare gene expression levels for 17 genes [including all 11 dopamine receptor interacting proteins, all 5 dopamine receptors (DRD1-DRD5) and DARPP-32] by real-time polymerase chain reaction, using prefrontal cortex post mortem brain samples from 33 schizophrenic, 32 bipolar disorder and 34 control subjects. the expression of C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 genes was altered in schizophrenia and/or bipolar disorder samples relative to controls (P < 0.05). Hierarchical clustering analysis revealed the expression of these five genes (C14ORF28, GNB2L1, MLLT3, DARPP-32, DRD2) is closely correlated in patients. However, in controls, DRD2 expression in relation to the other genes appears to be very different, suggesting abnormal DRD2 activity is an important trigger in the pathophysiology of schizophrenia and bipolar disorder. our data suggest: (i) C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 are important in the pathogenesis of schizophrenia and bipolar disorder; (ii) these two disorders share common disease-related mechanisms linked to dopamine signalling; (iii) the expression of these genes is closely correlated; and (iv) DRD2 provides the initial trigger in the pathogenesis of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 198 | Mol. Biol. Rep. 2011 Feb 38: 1407-11 |
| PMID | 20665240 |
| Title | Dopamine D2 receptor gene -141C Insertion/Deletion polymorphism in Turkish schizophrenic patients. |
| Abstract | schizophrenia is a chronic and neuropsychiatric disease that affects about 0.5-1% of the world's population. An increase in dopamine and dopamine D2 receptor (DRD2) gene products has been well described in schizophrenic patients. Several groups have studied the relationship between dopaminergic hyperactivity and cellular communications have obtained discordant results. Studies searching for the relationship between the schizophrenia and DRD2 gene have gained more interest. Our objective was to determine the relationships among schizophrenic symptoms in schizophrenia subtypes and severity of symptoms in terms of DRD2 gene -141C Insertion/Deletion [Ins/Del; I/D] polymorphism by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) assay method. Genomic DNA was prepared from peripheral blood by using salt extraction method. After amplification of genomic DNA, PCR products were digested with BstNI restriction enzyme for the detection of DRD2 gene -141C Ins/Del polymorphism in 73 schizophrenic patients and 60 healthy control subjects. The allelic frequencies of the DRD2 gene -141C Ins/Del polymorphism in case and control groups were 79.5 and 77.5% for I allele; 20.5 and 22.5% for D allele respectively. There was no significant difference in frequencies of genotypes and alleles between the two groups. In schizophrenic and control subjects, there were no significant relationship in severity of the disease and schizophrenia types among the -141C Ins/Del genotypes and alleles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 199 | 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 |
| 200 | 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 |
| 201 | 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 |
| 202 | Clin Psychopharmacol Neurosci 2012 Aug 10: 88-93 |
| PMID | 23429213 |
| Title | Assessment between Dopamine Receptor D2 (DRD2) Polymorphisms and Schizophrenia in Korean Population. |
| Abstract | The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of dopamine receptor D2 (DRD2) are associated with schizophrenia in Korean population. Four SNPs (rs4648317, rs7131056, rs4936270, and rs1076562) of DRD2 were selected and genotyped by direct sequencing in 197 schizophrenia patients and 370 control subjects. SNPAnalyzer, SNPStats, and Haploview version 4.2 programs were performed to analyze the genetic data. Multiple logistic regression models (codominant1, codominant2, dominant, recessive, overdominant, and log-additive) were used to evaluate the odds ratios (ORs), 95% confidence intervals (CIs), and p values. For multiple testing, p values (p(c)) were re-evaluated by Bonferroni's correction. The genotype frequency of DRD2 rs4936270 SNP was associated with the development of schizophrenia (p=0.0007, OR=1.71, 95% CI=1.16-2.52 in the codominant1 model; p=0.011, OR=1.63, 95% CI=1.12-2.37 in the dominant model; p=0.035, OR=1.41, 95% CI=1.03-1.95 in the log-additive model). The allele frequency of rs4936270 was also associated with the development of schizophrenia (p=0.024, OR=1.45, 95% CI=1.05-1.98). After Bonferroni's correction, the genotype distribution of rs4936270 was still related to the development of schizophrenia (p(c)=0.0028 in the codominant1 model; p(c)=0.044 in the dominant model). A linkage disequilibrium block consisted of rs4648317, rs7131056, and rs4936270. The CAT haplotype frequency was different between schizophrenia and controls (p=0.039). These results suggest that DRD2 SNPs may be associated with the development of schizophrenia in Korean population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 203 | Genet. Mol. Res. 2012 -1 11: 261-70 |
| PMID | 22370928 |
| Title | Association between Ser311Cys polymorphism in the dopamine D2 receptor gene and schizophrenia risk: a meta-analysis in Asian populations. |
| Abstract | Numerous studies have evaluated the association between Ser311Cys (rs1801028, C>G) polymorphism of the dopamine D2 receptor (DRD2) gene and schizophrenia risk. However, the specific association is still controversial. We examined whether DRD2 Ser311Cys polymorphism confers schizophrenia risk in Asian populations. Sixteen studies were retrieved reporting on a total of 2268 schizophrenia patients and 2423 healthy controls. Meta-analysis of the results showed significant associations between Ser311Cys polymorphism and schizophrenia risk in the comparisons of G versus C (odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.18-1.83, P = 0.0006) and CG+GG versus CC (OR = 1.45, 95%CI = 1.16- 1.82, P = 0.001). In a subgroup analysis by nationality, we found a significant association between Ser311Cys polymorphism and schizophrenia risk in the comparisons of G versus C and CG+GG versus CC genotype in the Japanese population (OR = 1.75, 95%CI = 1.30-2.35, P = 0.0002; OR = 1.72, 95%CI = 1.27-2.33, P = 0.0004; respectively) but not in Chinese and Indian populations. In conclusion, the G allele of DRD2 Ser311Cys polymorphism involves a potential risk factor for schizophrenia in Asian populations, especially in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 204 | Int. J. Neuropsychopharmacol. 2012 Nov 15: 1427-40 |
| PMID | 22244514 |
| Title | Sensorimotor gating and D2 receptor signalling: evidence from a molecular genetic approach. |
| Abstract | Converging evidence from pharmacological investigations, genetic association studies and schizophrenia research indicates an important influence of the dopamine system on sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response. In particular, D2 receptor agonists have been shown to disrupt PPI in humans and rodents. In the present study, we investigated the associations of two functional DRD2 related single nucleotide polymorphisms (rs4648317 and rs1800497, the latter also known as DRD2/ANKK1 Taq1A) with PPI in two independent healthy human samples (overall n=197; Munich n=101; London n=96). Taq1A is a prominent marker of striatal D2 receptor signalling and was therefore hypothesized to impact on PPI. In line with our hypothesis, we report here reduced PPI levels in individuals with higher striatal D2 receptor signalling as indicated by the Taq1A genotype. Meta-analysis across both samples confirmed this finding. In contrast, an association between rs4648317 and PPI found in the Munich sample could not be confirmed in the London sample. Overall, the present study helps to bridge the gap between pharmacological manipulations of PPI and molecular genetics of the dopaminergic system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 205 | 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 |
| 206 | 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 |
| 207 | Psychiatry Clin. Neurosci. 2012 Oct 66: 518-24 |
| PMID | 23066770 |
| Title | Prolactin concentrations during aripiprazole treatment in relation to sex, plasma drugs concentrations and genetic polymorphisms of dopamine D2 receptor and cytochrome P450 2D6 in Japanese patients with schizophrenia. |
| Abstract | The authors investigated the correlation between prolactin concentrations during aripiprazole treatment and various factors, including age, sex, plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, and genetic polymorphisms of dopamine D2 receptor (DRD2) and cytochrome P450(CYP)2D6. The subjects were 70 inpatients with schizophrenia (36 men and 34 women), receiving fixed doses of aripiprazole (24 mg in 45 cases and 12 mg in 25 cases) for periods of between 2 and 30 weeks. Prolactin concentrations were measured by chemiluminescence immunoassay. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The genotypes of Taq1A, -141C Ins/Del DRD2 and CYP2D6 were detected by polymerase chain reaction methods. Prolactin concentrations were significantly higher in women than in men (8.9 ± 7.5 vs 3.4 ± 3.0 ng/mL, P < 0.001). No correlations were found between prolactin concentrations and plasma concentrations of aripiprazole, dehydroaripiprazole or the sum of the two compounds. Prolactin concentrations were not affected by any polymorphism. The present study suggests that only sex plays a significant role in prolactin concentrations during aripiprazole treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 208 | Pharmacogenomics J. 2012 Apr 12: 156-64 |
| PMID | 20714340 |
| Title | Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. |
| Abstract | Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 209 | Genet Test Mol Biomarkers 2012 Feb 16: 77-81 |
| PMID | 21861710 |
| Title | A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset: HapMap tag-single-nucleotide polymorphism analysis. |
| Abstract | Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain, which is known to be important in the etiology of schizophrenia. It is, therefore, not surprising that most antipsychotic medication acts on DRD2. DRD2 is widely expressed in the brain; levels are reduced in the brains of patients with schizophrenia, and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single-nucleotide polymorphisms (SNPs) in DRD2 by using a multiplex mass spectrometry method. SNPs were chosen by using a haplotype block-based gene-tagging approach; so, the entire DRD2 gene was represented. One polymorphism, rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared with controls. Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor of age of onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 210 | J Clin Psychiatry 2012 Aug 73: 1077-86 |
| PMID | 22967772 |
| Title | Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia. |
| Abstract | Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population. The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure. The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found. Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 211 | Neurosci. Lett. 2012 Jun 518: 41-4 |
| PMID | 22569179 |
| Title | Rs1076560, a functional variant of the dopamine D2 receptor gene, confers risk of schizophrenia in Han Chinese. |
| Abstract | The dopamine receptor genes have been implicated in the pathogenesis of schizophrenia, but definitive evidence of association is still lacking. To identify whether functional variants of the D2-like receptors (DRD2, DRD3 and DRD4) confer risk of schizophrenia, we conducted a two-stage association study. We firstly examined the SNPs in functional genomic regions, such as mRNA splicing, protein coding and the promoter regions in DRD2, DRD3 and DRD4, respectively, for association in 289 Han Chinese cases with schizophrenia and 367 healthy controls and then further analyzed the significantly associated single nucleotide polymorphisms (SNPs) with this disorder in an additional Han Chinese sample consisted of 1351 cases and 1640 control subjects. In the first stage, the chi-square test (?(2)) showed disease association for rs1076560 in DRD2 (p=0.040 for allelic association and p=0.033 for genotypic association, respectively). However, rs6280 in DRD3 and rs3758653 in DRD4 failed to show either allelic or genotypic association with the illness. The association between rs1076560 and schizophrenia was replicated in the second stage. The rs1076560-T allele, which shifts splicing from the D2 short isoform (D2S) to the D2 long isoform (D2L), was over-presented in the patient group (44%) than in the control group (41%) (?(2)=5.19, p=0.023, OR=1.13, 95% CI=1.02-1.25). Therefore, the rs1076560 variant of DRD2 reliably influences risk of schizophrenia in Han Chinese, although more data are required to elucidate the pathophysiological mechanisms of possessing this risk-conferring variant. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 212 | J Clin Psychopharmacol 2012 Feb 32: 106-9 |
| PMID | 22198450 |
| Title | Effects of aripiprazole and the Taq1A polymorphism in the dopamine D2 receptor gene on the clinical response and plasma monoamine metabolites level during the acute phase of schizophrenia. |
| Abstract | The Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene could be related to the response to antipsychotics. We examined the effects of the Taq1A polymorphism on the plasma monoamine metabolites during the treatment of schizophrenia with aripiprazole, a DRD2 partial agonist. Thirty Japanese patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol (pMHPG) before and after treatment. The Taq1A polymorphism was genotyped with polymerase chain reaction. Aripiprazole improved the acute symptoms of schizophrenia and decreased pHVA in responders (P = 0.023) but not in nonresponders (P = 0.28). Although A1 allele carriers showed a tendency to respond to aripiprazole (61.5%) compared to A1 allele noncarriers (29.4%) (P = 0.078), there was not statistically significant difference in the response between the 2 genotype groups. There were significant effect for response (P = 0.013) and genotype × response interaction (P = 0.043) on the change of pHVA. The changes of pHVA differ between responders and nonresponders in A1 allele carriers but not in A1 allele noncarriers. There were no genotype or response effects or genotype × response interaction on the changes of the plasma levels of 3-methoxy-4hydroxyphenylglycol. Our preliminary results suggest that Taq1A polymorphism may be partly associated with changes in pHVA during acute schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 213 | Mol. Psychiatry 2012 Mar 17: 242-66 |
| PMID | 21894153 |
| Title | Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. |
| Abstract | Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 214 | 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 |
| 215 | Psychopharmacology (Berl.) 2012 Feb 219: 727-36 |
| PMID | 21750899 |
| Title | Association of two DRD2 gene polymorphisms with acute and tardive antipsychotic-induced movement disorders in young Caucasian patients. |
| Abstract | Pharmacogenetic studies on antipsychotic-induced movement disorders (MD) in schizophrenia so far have focused mainly on tardive dyskinesia. Only a few examined the more acute antipsychotic-induced MD such as parkinsonism and akathisia. Notably, all MD relate to deregulation of the dopamine system. This study aimed to replicate previously reported associations in candidate genes for acute and tardive antipsychotic-induced MD in a young Caucasian sample. In 402 patients (median age 26 years), a total of 13 polymorphisms were genotyped in eight dopamine-related candidate genes selected a priori from the literature (regarding dopamine and serotonin receptors, dopamine degradation, and free radicals scavenging enzymes pathways). Patients with MD used on average a higher haloperidol dose equivalent when compared to those without MD. The prevalence of MD was high and did not differ between first- and second-generation antipsychotics. Significant associations were found between (a) the TaqI_D polymorphism and akathisia (OR?=?2.3, p?=?0.001 for each extra C-allele) and (b) the -141C polymorphism and tardive dyskinesia (OR?=?0.20, p?=?0.001 for each extra Del allele). The other polymorphisms were not significantly associated with an MD. Two associations were found between genetic variation TaqI_D and the -141C polymorphisms in the DRD2 gene and antipsychotic-induced MD; one with acute akathisia and one with tardive dyskinesia. These were previously reported to be associated with tardive dyskinesia and acute parkinsonism, respectively. These results suggest that the contribution of these DRD2 gene variants in the vulnerability of antipsychotic-induced MD takes place in a more general or pleiotropic way. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 216 | J. Psychopharmacol. (Oxford) 2012 Feb 26: 324-9 |
| PMID | 21262859 |
| Title | Alcohol Use Disorders Identification Test (AUDIT) scores are elevated in antipsychotic-induced hyperprolactinaemia. |
| Abstract | Hyperprolactinaemia in antipsychotic treated patients with schizophrenia is a consequence of D2 receptor (DRD2) blockade. Alcohol use disorder is commonly comorbid with schizophrenia and low availability of striatal DRD2 may predispose individuals to alcohol use. In this pilot study we investigated whether hyperprolactinaemia secondary to pharmacological DRD2 blockade was associated with alcohol use disorder in 219 (178 males and 41 females) patients with schizophrenia. Serum prolactin determinations were made in patients diagnosed with schizophrenia and maintained on antipsychotic agents. Clinical assessment included demographics, family history and administration of the AUDIT (Alcohol Use Disorders Identification Test). Higher AUDIT scores were associated with prolactin-raising antipsychotic medication (n=106) compared with prolactin-sparing medication (n=113). Risperidone (n=63) treated patients had higher AUDIT scores and prolactin levels than those on other atypical antipsychotics (n = 113). Across the entire sample, patients with a prolactin greater than 800 mIU/L had higher AUDIT scores and were more likely to exceed the cut-off score for harmful and hazardous alcohol use. These differences were not explained by potential confounds related to clinical features and demographics, comorbidity or medication side-effects. These data suggest that by lowering dosage, or switching to another antipsychotic agent, the risk for alcohol use disorder in those with schizophrenia may be reduced. This hypothesis requires testing using a prospective methodology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 217 | 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 |
| 218 | J Clin Psychopharmacol 2012 Aug 32: 441-8 |
| PMID | 22722500 |
| Title | Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response. |
| Abstract | Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study. Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses. Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response. We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 219 | J. Hum. Genet. 2013 Apr 58: 182 |
| PMID | 23446888 |
| Title | A commentary on DRD2 haplotype associated with negative symptoms and sustained attention deficits in Han Chinese with schizophrenia in Taiwan. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 220 | 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 |
| 221 | Psychiatr. Genet. 2013 Oct 23: 183-7 |
| PMID | 23851595 |
| Title | Analysis of association between dopamine receptor genes' methylation and their expression profile with the risk of schizophrenia. |
| Abstract | schizophrenia (SCZ) is a type of psychotic disorder that affects ~1% of the population. Dopamine is one of the major neurotransmitters in the brain and its receptors are associated with a number of psychotic disorders, including SCZ. The aims of the present study were to analyze methylation and the expression profile of dopamine receptor DRD1, DRD2, DRD4, and DRD5 genes in patients with SCZ. Promoter methylation of DRD1, DRD2, DRD4, and DRD5 genes was assayed by a methylation-specific PCR in blood samples obtained from 80 SCZ cases and 71 healthy controls. Also, we investigated DRD1, DRD2, DRD4, and DRD5 mRNA levels using real-time reverse transcription PCR in 34 blood samples of healthy controls and cases. Promoter methylation of DRD4, DRD5, and DRD2 genes was statistically different in cases compared with healthy controls. The mRNA expression level results also showed statistically significant differences (P<0.0001) between cases and healthy controls for the DRD2, DRD4, and DRD5 genes, but not for DRD1. Analyses of DRD genes' methylation have highlighted the fact that the DRD gene network, overall, is actively involved in the increased risk of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 222 | Schizophr Bull 2013 Jul 39: 766-75 |
| PMID | 23512949 |
| Title | Clinical and molecular genetics of psychotic depression. |
| Abstract | This review provides a comprehensive overview of clinical and molecular genetic as well as pharmacogenetic studies regarding the clinical phenotype of "psychotic depression." Results are discussed with regard to the long-standing debate on categorical vs dimensional disease models of affective and psychotic disorders on a continuum from unipolar depression over bipolar disorder and schizoaffective disorder to schizophrenia. Clinical genetic studies suggest a familial aggregation and a considerable heritability (39%) of psychotic depression partly shared with schizoaffective disorder, schizophrenia, and affective disorders. Molecular genetic studies point to potential risk loci of psychotic depression shared with schizoaffective disorder (1q42, 22q11, 19p13), depression, bipolar disorder, and schizophrenia (6p, 8p22, 10p13-12, 10p14, 13q13-14, 13q32, 18p, 22q11-13) and several vulnerability genes possibly contributing to an increased risk of psychotic symptoms in depression (eg, BDNF, DBH, DTNBP1, DRD2, DRD4, GSK-3beta, MAO-A). Pharmacogenetic studies implicate 5-HTT, TPH1, and DTNBP1 gene variation in the mediation of antidepressant treatment response in psychotic depression. Genetic factors are suggested to contribute to the disease risk of psychotic depression in partial overlap with disorders along the affective-psychotic spectrum. Thus, genetic research focusing on psychotic depression might inspire a more dimensional, neurobiologically and symptom-oriented taxonomy of affective and psychotic disorders challenging the dichotomous Kraepelinian view. Additionally, pharmacogenetic studies might aid in the development of a more personalized treatment of psychotic depression with an individually tailored antidepressive/antipsychotic pharmacotherapy according to genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 223 | Schizophr. Res. 2013 Oct 150: 262-5 |
| PMID | 23899995 |
| Title | Hypomethylation of neuregulin in rats selectively bred for reduced sensorimotor gating. |
| Abstract | Low prepulse inhibition (PPI) of startle is associated with reduced sensorimotor gating found in schizophrenia. In rats with breeding-induced low PPI neuregulin (NRG1) methylation was significantly decreased in brain regions associated with this phenotype and with schizophrenia, i.e., the medial prefrontal cortex, the nucleus accumbens, and the ventral hippocampus, while methylation in the amygdala and dorsal hippocampus was less affected. The dopamine D2 receptor (DRD2) promoter region showed negligible changes between groups. Rats with low PPI may be used to understand the reduced epigenetic regulation found in schizophrenia, and eventually lead to the development of novel therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 224 | 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 |
| 225 | Neuropsychopharmacology 2013 Jul 38: 1512-20 |
| PMID | 23422792 |
| Title | D-amphetamine and antipsychotic drug effects on latent inhibition in mice lacking dopamine D2 receptors. |
| Abstract | Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D2 is necessary for their behavioral effects. Using D2-null mice (DRD2-/-), we first investigated whether D2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and DRD2-/-. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in DRD2-/-. AMP disruption of LI was attenuated in mice lacking dopamine receptor D1 (Drd1-/-), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in DRD2-/-. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D2 receptors. Data suggest that D2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D1 merits investigation in the mediation of AMP disruption of these processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 226 | PLoS ONE 2013 -1 8: e75259 |
| PMID | 24086483 |
| Title | Identification of the mRNA expression status of the dopamine D2 receptor and dopamine transporter in peripheral blood lymphocytes of schizophrenia patients. |
| Abstract | The aim of this study was to detect the mRNA expression levels of the dopamine D2 receptor (DRD2) and dopamine transporter (DAT) in peripheral blood leukocytes (PBLs) of schizophrenia patients and to explore the relationship between the mRNA expression levels and the clinical symptoms of schizophrenia. The research included 25 cases of acute schizophrenia patients, 27 cases of chronic schizophrenia patients, and 30 healthy controls. In every case, we measured the mRNA levels of DRD2 and DAT in PBLs by real-time quantitative reverse transcription-polymerase chain reaction (real-time RT-PCR), and we evaluated the patients' clinical symptoms using the Positive and Negative Syndrome Scale (PANSS). DRD2 mRNA levels in PBLs of acute schizophrenia patients, chronic schizophrenia patients, and healthy controls were 0.32±0.13, 0.37±0.19, and 0.34±0.09, respectively, and the difference was not significant. DAT mRNA levels in PBLs of the abovementioned groups were 0.48±0.24, 0.58±0.21 and 0.39±0.24, respectively (F?=?4.330, P?=?0.017), and comparisons between every group showed that DAT mRNA levels in PBLs of chronic schizophrenia patients were significantly higher than those in healthy controls (MS interclass?=?0.198, p?=?0.005). The correlation between DRD2 mRNA levels in PBLs and the positive symptom points of PANSS in acute schizophrenia patients was significant (r?=?0.443, p?=?0.044). In conclusion, DRD2 mRNA levels in PBLs are correlated with positive symptoms in acute schizophrenia patients, and DAT mRNA levels in PBLs of chronic schizophrenia patients are over-expressed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 227 | 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 |
| 228 | J. Int. Med. Res. 2013 Aug 41: 1171-8 |
| PMID | 23816932 |
| Title | Functional -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter and schizophrenia in a Chinese Han population. |
| Abstract | The association between a putative functional promoter polymorphism, -141C insertion/deletion (Ins/Del), in the dopamine receptor D2 gene (DRD2) and schizophrenia was investigated in a Chinese Han population. The polymorphism was studied in unrelated schizophrenia patients and unrelated healthy controls. Linkage relationships were explored in core families of the schizophrenic patients using the transmission disequilibrium test. The Positive and Negative Syndrome Scale was used to evaluate the severity of the disorder. The Del allele was significantly less frequently found in patients (13/120; 11%) than in controls (18/100; 18%). In the 32 core families studied, 16 parents were Ins/Del heterozygotes. Parents transmitted the Ins and Del alleles to their children in 10 and six cases, respectively. Data from core families did not demonstrate linkage. Age, age at onset of schizophrenia and sex were not significantly different between carriers of the Ins and Del alleles. The group with the Ins allele had a significantly higher positive symptom score (75.3 ± 23.4 versus 53.9 ± 21.9) and excitement score (83.6 ± 16.8 versus 50.3 ± 24.6) than the Del group. Groups did not differ significantly in negative symptom and general psychopathology scores. The DRD2 -141C Ins/Del polymorphism may affect susceptibility to schizophrenia in a Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 229 | Front Hum Neurosci 2013 -1 7: 130 |
| PMID | 23596404 |
| Title | Dopaminergic basis of the psychosis-prone personality investigated with functional magnetic resonance imaging of procedural learning. |
| Abstract | Previous evidence shows a reliable association between psychosis-prone (especially schizotypal) personality traits and performance on dopamine (DA)-sensitive tasks (e.g., prepulse inhibition and antisaccade). Here, we used blood oxygen level-dependent (BOLD) fMRI and an established procedural learning (PL) task to examine the dopaminergic basis of two aspects of psychosis-proneness (specific schizotypy and general psychoticism). Thirty healthy participants (final N = 26) underwent fMRI during a blocked, periodic sequence-learning task which, in previous studies, has been shown to reveal impaired performance in schizophrenia patients given drugs blocking the DA D2 receptor subtype (DRD2), and to correspond with manipulation of DA activity and elicit fronto-striatal-cerebellar activity in healthy people. Psychosis-proneness was indexed by the Psychoticism (P) scale of the Eysenck Personality Questionnaire-Revised (EPQ-R; 1991) and the schizotypal Personality Scale (STA; 1984). EPQ-R Extraversion and Neuroticism scores were also examined to establish discriminant validity. We found a positive correlation between the two psychosis-proneness measures (r = 0.43), and a robust and unique positive association between EPQ-R P and BOLD signal in the putamen, caudate, thalamus, insula, and frontal regions. STA schizotypy score correlated positively with activity in the right middle temporal gyrus. As DA is a key transmitter in the basal ganglia, and the thalamus contains the highest levels of DRD2 receptors of all extrastriatal regions, our results support a dopaminergic basis of psychosis-proneness as measured by the EPQ-R Psychoticism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 230 | J Psychiatr Res 2013 Jul 47: 926-34 |
| PMID | 23540600 |
| Title | Analysis of Sp transcription factors in the postmortem brain of chronic schizophrenia: a pilot study of relationship to negative symptoms. |
| Abstract | Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamine and glutamate pathways has been proposed for the emergence of these symptoms. SP1, SP3 and SP4 transcription factors regulate genes in these pathways, suggesting a possible involvement in negative symptoms. In this study, we characterized Sp factors in the brains of subjects with schizophrenia and explored a possible association with negative symptoms. We also included analysis of NR1, NR2A and DRD2 as Sp target genes. Postmortem cerebellum and prefrontal cortex from an antemortem clinically well-characterized and controlled collection of elderly subjects with chronic schizophrenia (n = 16) and control individuals (n = 14) were examined. We used the Positive and Negative Syndrome and the Clinical Global Impression schizophrenia scales, quantitative PCR and immunoblot. SP1 protein and mRNA were reduced in the prefrontal cortex in schizophrenia whereas none of Sp factors were altered in the cerebellum. However, we found that SP1, SP3 and SP4 protein levels inversely correlated with negative symptoms in the cerebellum. Furthermore, NR2A and DRD2 mRNA levels correlated with negative symptoms in the cerebellum. In the prefrontal cortex, SP1 mRNA and NR1 and DRD2 inversely correlated with these symptoms while Sp protein levels did not. This pilot study not only reinforces the involvement of SP1 in schizophrenia, but also suggests that reduced levels or function of SP1, SP4 and SP3 may participate in negative symptoms, in part through the regulation of NMDA receptor subunits and/or Dopamine D2 receptor, providing novel information about the complex negative symptoms in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 231 | J. Hum. Genet. 2013 Apr 58: 229-32 |
| PMID | 23364393 |
| Title | DRD2 haplotype associated with negative symptoms and sustained attention deficits in Han Chinese with schizophrenia in Taiwan. |
| Abstract | Previous studies have reported significant associations between schizophrenia and the dopamine receptor D2 gene (DRD2) variants. The relationships between DRD2 and clinical phenotypes are of particular interest because DRD2 has been shown to associate with treatment response and prefrontal dopamine transmission. Glatt et al. reported significant associations between schizophrenia and DRD2 variants (two single-nucleotide polymorphisms (SNPs) rs1079727 and rs2283265, and two haplotypes, block 3 (rs1079727(A)-rs2440390(C)-rs2283265(G)) and block 4 (rs1801028(G)-rs1110977(A)-rs1124492(C)-rs2734841 (T))) in 2408 Han Chinese individuals in Taiwan. To further investigate the relationships between the SNPs/haplotypes of DRD2 and clinical symptoms and neuropsychological function, we compared the quantitative phenotypes in patients with risk alleles/haplotypes and those without. The results showed that the A allele of rs1079727, G allele of rs2283265, A allele of rs1124492 and the risk haplotype (A-C-G) of block 3 were associated with more severe negative symptoms. With regard to neuropsychological performance, the risk haplotype (G-A-C-T) of block 4 was associated with poorer performance in the sustained attention task. Our results imply that the genetic variants of DRD2 might not only have a role in susceptibility to schizophrenia, but also influence the phenotypes of negative symptoms and sustained attention in schizophrenia. This association warrants further validation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 232 | J Mol Psychiatry 2013 -1 1: 19 |
| PMID | 25408910 |
| Title | Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis. |
| Abstract | The dopamine (DA) hypothesis of schizophrenia proposes the mental illness is caused by excessive transmission of dopamine in selected brain regions. Multiple lines of evidence, including blockage of dopamine receptors by antipsychotic drugs that are used to treat schizophrenia, support the hypothesis. However, the dopamine D2 receptor (DRD2) blockade cannot explain some important aspects of the therapeutic effect of antipsychotic drugs. In this study, we hypothesized that antipsychotic drugs could affect the transcription of genes in the DA pathway by altering their epigenetic profile. To test this hypothesis, we examined the effect of olanzapine, a commonly used atypical antipsychotic drug, on the DNA methylation status of genes from DA neurotransmission in the brain and liver of rats. Genomic DNA isolated from hippocampus, cerebellum, and liver of olanzapine treated (n?=?2) and control (n?=?2) rats were analyzed using rat specific methylation arrays. Our results show that olanzapine causes methylation changes in genes encoding for DA receptors (dopamine D1 receptor, dopamine D2 receptor and dopamine D5 receptor), a DA transporter (solute carrier family 18 member 2), a DA synthesis (differential display clone 8), and a DA metabolism (catechol-O-methyltransferase). We assessed a total of 40 genes in the DA pathway and found 19 to be differentially methylated between olanzapine treated and control rats. Most (17/19) genes showed an increase in methylation, in their promoter regions with in silico analysis strongly indicating a functional potential to suppress transcription in the brain. Our results suggest that chronic olanzapine may reduce DA activity by altering gene methylation. It may also explain the delayed therapeutic effect of antipsychotics, which occurs despite rapid dopamine blockade. Furthermore, given the common nature of epigenetic variation, this lends insight into the differential therapeutic response of psychotic patients who display adequate blockage of dopamine receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 233 | 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 |
| 234 | J. Int. Med. Res. 2013 Aug 41: 1171-8 |
| PMID | 23816932 |
| Title | Functional -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter and schizophrenia in a Chinese Han population. |
| Abstract | The association between a putative functional promoter polymorphism, -141C insertion/deletion (Ins/Del), in the dopamine receptor D2 gene (DRD2) and schizophrenia was investigated in a Chinese Han population. The polymorphism was studied in unrelated schizophrenia patients and unrelated healthy controls. Linkage relationships were explored in core families of the schizophrenic patients using the transmission disequilibrium test. The Positive and Negative Syndrome Scale was used to evaluate the severity of the disorder. The Del allele was significantly less frequently found in patients (13/120; 11%) than in controls (18/100; 18%). In the 32 core families studied, 16 parents were Ins/Del heterozygotes. Parents transmitted the Ins and Del alleles to their children in 10 and six cases, respectively. Data from core families did not demonstrate linkage. Age, age at onset of schizophrenia and sex were not significantly different between carriers of the Ins and Del alleles. The group with the Ins allele had a significantly higher positive symptom score (75.3 ± 23.4 versus 53.9 ± 21.9) and excitement score (83.6 ± 16.8 versus 50.3 ± 24.6) than the Del group. Groups did not differ significantly in negative symptom and general psychopathology scores. The DRD2 -141C Ins/Del polymorphism may affect susceptibility to schizophrenia in a Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 235 | Eur Arch Psychiatry Clin Neurosci 2013 Feb 263: 65-74 |
| PMID | 22893251 |
| Title | Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol. |
| Abstract | The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 236 | 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 |
| 237 | Front Hum Neurosci 2013 -1 7: 130 |
| PMID | 23596404 |
| Title | Dopaminergic basis of the psychosis-prone personality investigated with functional magnetic resonance imaging of procedural learning. |
| Abstract | Previous evidence shows a reliable association between psychosis-prone (especially schizotypal) personality traits and performance on dopamine (DA)-sensitive tasks (e.g., prepulse inhibition and antisaccade). Here, we used blood oxygen level-dependent (BOLD) fMRI and an established procedural learning (PL) task to examine the dopaminergic basis of two aspects of psychosis-proneness (specific schizotypy and general psychoticism). Thirty healthy participants (final N = 26) underwent fMRI during a blocked, periodic sequence-learning task which, in previous studies, has been shown to reveal impaired performance in schizophrenia patients given drugs blocking the DA D2 receptor subtype (DRD2), and to correspond with manipulation of DA activity and elicit fronto-striatal-cerebellar activity in healthy people. Psychosis-proneness was indexed by the Psychoticism (P) scale of the Eysenck Personality Questionnaire-Revised (EPQ-R; 1991) and the schizotypal Personality Scale (STA; 1984). EPQ-R Extraversion and Neuroticism scores were also examined to establish discriminant validity. We found a positive correlation between the two psychosis-proneness measures (r = 0.43), and a robust and unique positive association between EPQ-R P and BOLD signal in the putamen, caudate, thalamus, insula, and frontal regions. STA schizotypy score correlated positively with activity in the right middle temporal gyrus. As DA is a key transmitter in the basal ganglia, and the thalamus contains the highest levels of DRD2 receptors of all extrastriatal regions, our results support a dopaminergic basis of psychosis-proneness as measured by the EPQ-R Psychoticism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 238 | Front Hum Neurosci 2013 -1 7: 130 |
| PMID | 23596404 |
| Title | Dopaminergic basis of the psychosis-prone personality investigated with functional magnetic resonance imaging of procedural learning. |
| Abstract | Previous evidence shows a reliable association between psychosis-prone (especially schizotypal) personality traits and performance on dopamine (DA)-sensitive tasks (e.g., prepulse inhibition and antisaccade). Here, we used blood oxygen level-dependent (BOLD) fMRI and an established procedural learning (PL) task to examine the dopaminergic basis of two aspects of psychosis-proneness (specific schizotypy and general psychoticism). Thirty healthy participants (final N = 26) underwent fMRI during a blocked, periodic sequence-learning task which, in previous studies, has been shown to reveal impaired performance in schizophrenia patients given drugs blocking the DA D2 receptor subtype (DRD2), and to correspond with manipulation of DA activity and elicit fronto-striatal-cerebellar activity in healthy people. Psychosis-proneness was indexed by the Psychoticism (P) scale of the Eysenck Personality Questionnaire-Revised (EPQ-R; 1991) and the schizotypal Personality Scale (STA; 1984). EPQ-R Extraversion and Neuroticism scores were also examined to establish discriminant validity. We found a positive correlation between the two psychosis-proneness measures (r = 0.43), and a robust and unique positive association between EPQ-R P and BOLD signal in the putamen, caudate, thalamus, insula, and frontal regions. STA schizotypy score correlated positively with activity in the right middle temporal gyrus. As DA is a key transmitter in the basal ganglia, and the thalamus contains the highest levels of DRD2 receptors of all extrastriatal regions, our results support a dopaminergic basis of psychosis-proneness as measured by the EPQ-R Psychoticism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 239 | 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 |
| 240 | Neuropharmacology 2014 Aug 83: 1-8 |
| PMID | 24704148 |
| Title | Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. |
| Abstract | Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for at least several months after cessation of treatment. The behaviors are consistent with those observed in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction. In order to elucidate molecular changes that underlie these aberrant behaviors, we chronically treated rats with LSD and performed RNA-sequencing on the medial prefrontal cortex (mPFC), an area highly associated with both the actions of LSD and the pathophysiology of schizophrenia and other psychiatric illnesses. We observed widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes observed with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering analysis indicates differentially expressed genes are enriched in pathways involving neurotransmission (DRD2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metabolism (Atp5d, Ndufa1) and neuropeptide signaling (Npy, Bdnf), among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia, and genes affected by LSD are enriched with putative schizophrenia genes. Our results provide a relatively comprehensive analysis of mPFC transcriptional regulation in response to chronic LSD, and indicate that the long-term effects of LSD may bear relevance to psychiatric illnesses, including schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 241 | Neuroscience 2014 Feb 260: 265-75 |
| PMID | 24345476 |
| Title | Lack of BDNF expression through promoter IV disturbs expression of monoamine genes in the frontal cortex and hippocampus. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of psychiatric conditions including major depression and schizophrenia. Mice lacking activity-driven BDNF expression through promoter IV (knock-in promoter IV: KIV) exhibit depression-like behavior, inflexible learning, and impaired response inhibition. Monoamine systems (serotonin, dopamine, and noradrenaline) are suggested to be involved in depression and schizophrenia since many of the current antidepressants and antipsychotics increase the brain levels of monoamines and/or act on monoamine receptors. To elucidate the impact of activity-driven BDNF on the monoamine systems, we examined mRNA levels for 30 monoamine-related genes, including receptors, transporters, and synthesizing enzymes, in KIV and control wild-type mice by using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). mRNA levels were measured in the frontal cortex and hippocampus, which are regions related to depression and schizophrenia and where promoter IV is active. The frontal cortex of KIV mice showed reduced levels of mRNA expression for serotonin receptors 1b, 2a, and 5b (5HTR1b, 5HTR2a, 5HTR5b), dopamine D2 receptors (DRD2), and adrenergic receptors alpha 1a and 1d (AdR?1a and AdR?1b), but increased levels for serotonin synthesizing enzyme, tryptophan hydroxylase (TPH), and dopamine D4 receptor (DRD4) when compared to control wild-type mice. The hippocampus of KIV mice showed decreased levels of 5HTR5b. Our results provide causal evidence that lack of promoter IV-driven BDNF disturbs expression of monoaminergic genes in the frontal cortex and hippocampus. These disturbed expression changes in the monoamine systems may mediate the depression- and schizophrenia-like behavior of KIV mice. Our results also suggest that antidepressant and antipsychotic treatments may actually interfere with and normalize the disturbed monoamine systems caused by reduced activity-dependent BDNF, while the treatment responses to these drugs may differ in the subject with reduced BDNF levels caused by stress and lack of neuronal activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 242 | Neurosci. Lett. 2014 Nov 583: 43-8 |
| PMID | 25240594 |
| Title | The relationship between DRD2 gene polymorphisms (C957T and C939T) and schizophrenia: a meta-analysis. |
| Abstract | schizophrenia is a common, complex multi-factorial psychiatric disorder. Many studies have reported associations between the C957T and C939T polymorphisms in Dopamine D2 receptor (DRD2) gene and schizophrenia, but results are inconsistent. To derive a more precise estimation of the relationship, a meta-analysis was conducted to systematically summarize the possibility. We included 13 articles involving 3079 schizophrenia cases and 3851 healthy controls. Positive associations were found between C957T polymorphism and schizophrenia risk in C vs. T (OR=1.26, 95% CI=1.09-1.46, Praw=0.002, PFDR=0.005) and CC+CT vs. TT (OR=1.47, 95% CI=1.25-1.73, Praw<0.001, PFDR<0.001). When stratified by race, a significantly increased risk of schizophrenia was observed in Caucasians, but not in Asians. No association between C939T polymorphism and schizophrenia was found in overall or Asian population. Our study suggested that C957T of DRD2 gene polymorphism is likely to be a risk factor for schizophrenia, especially in Caucasian. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 243 | Schizophr. Res. 2014 Aug 157: 163-8 |
| PMID | 24893910 |
| Title | Effect of antipsychotic drugs on gene expression in the prefrontal cortex and nucleus accumbens in the spontaneously hypertensive rat (SHR). |
| Abstract | Antipsychotic drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was DRD2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 244 | Recent Pat Biotechnol 2014 -1 8: 152-9 |
| PMID | 25185985 |
| Title | Pharmacogenomics in psychiatry: implications for practice. |
| Abstract | Psychotropic medications are used for numerous psychiatric and neurologic disorders, and are associated with in some cases life-threatening adverse effects, high acquisition costs, stringent monitoring requirements, and potential interactions with other medications. Because of the risks of adverse effects and need for adherence, risk mitigation strategies are being implemented to protect consumers. An understanding of receptor activities, cytochrome P450 2D6 and 2C19 metabolism, overlapping pharmacology, and polymorphic biomarkers for the dopamine 2 D2 receptor gene (DRD2) and dopamine 3 D3 receptor gene (DRD3), serotonin 2A and 2C receptor genes (5HTR2A and 5HTR2C), and human leukocyte antigen (HLA) variants creates opportunities for the integration of pharmacogenomics, and can assist in the application of personalized medicine in this arena. In this review, we discuss the current impression of pharmacogenomic principles pertaining to select psychotropics, with attention given to the atypical antipsychotics, due to their wide use across a broad spectrum of psychiatric disorders (e.g. bipolar disorder, depression, schizophrenia). Patents involving aripiprazole, clozapine, olanzapine, and risperidone will be discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 245 | Arq Neuropsiquiatr 2014 Aug 72: 582-6 |
| PMID | 25098474 |
| Title | Association study between the Taq1A (rs1800497) polymorphism and schizophrenia in a Brazilian sample. |
| Abstract | schizophrenia is a severe psychotic disorder with recurrent relapse and functional impairment. It results from a poorly understood gene-environment interaction. The Taq1A polymorphism (located in the gene cluster NTAD) is a likely candidate for schizophrenia. Its rs1800497 polymorphism was shown to be associated with DRD2 gene expression. Therefore the present work aims to investigate a possible association between schizophrenia and such polymorphism. The compared distribution of the alleles and genotypes of the studied polymorphism was investigated in a Brazilian sample of 235 patients and 834 controls. Genotypic frequencies were in Hardy-Weinberg equilibrium. There was a trend of allelic association between the Taq1A polymorphism (rs1800497) with schizophrenia in the studied sample. However no statistically differences were found between cases and controls when analyzed by gender or schizophrenia subtypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 246 | Nature 2014 Jul 511: 421-7 |
| PMID | 25056061 |
| Title | Biological insights from 108 schizophrenia-associated genetic loci. |
| Abstract | schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 247 | Science 2014 Jun 344: 1178-82 |
| PMID | 24904170 |
| Title | Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. |
| Abstract | Auditory hallucinations in schizophrenia are alleviated by antipsychotic agents that inhibit D2 dopamine receptors (DRD2s). The defective neural circuits and mechanisms of their sensitivity to antipsychotics are unknown. We identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an aberrant elevation of DRD2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the DRD2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. This suggests that Dgcr8-microRNA-DRD2-dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 248 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Aug 53: 123-8 |
| PMID | 24704945 |
| Title | Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism. |
| Abstract | Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia. We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANKK1) gene. We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P<0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms. These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 249 | 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 |
| 250 | Mol. Psychiatry 2014 Dec 19: 1258-66 |
| PMID | 24322206 |
| Title | Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain. |
| Abstract | Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (~700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P<0.0001 and P<0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P<0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P<0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P<0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P<0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 251 | Front Endocrinol (Lausanne) 2014 -1 5: 129 |
| PMID | 25183960 |
| Title | Apo-Ghrelin Receptor (apo-GHSR1a) Regulates Dopamine Signaling in the Brain. |
| Abstract | The orexigenic peptide hormone ghrelin is synthesized in the stomach and its receptor growth hormone secretagogue receptor (GHSR1a) is expressed mainly in the central nervous system (CNS). In this review, we confine our discussion to the physiological role of GHSR1a in the brain. Paradoxically, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain. In our efforts to elucidate the function of the ligand-free ghrelin receptor (apo-GHSR1a), we identified subsets of neurons that co-express GHSR1a and dopamine receptors. In this review, we focus on interactions between apo-GHSR1a and dopamine-2 receptor (DRD2) and formation of GHSR1a:DRD2 heteromers in hypothalamic neurons that regulate appetite, and discuss implications for the treatment of Prader-Willi syndrome (PWS). GHSR1a antagonists of distinct chemical structures, a quinazolinone and a triazole, respectively, enhance and inhibit dopamine signaling through GHSR1a:DRD2 heteromers by an allosteric mechanism. This finding illustrates a potential strategy for designing the next generation of drugs for treating eating disorders as well as psychiatric disorders caused by abnormal dopamine signaling. Treatment with a GHSR1a antagonist that enhances dopamine/DRD2 activity in GHSR1a:DRD2 expressing hypothalamic neurons has the potential to inhibit the uncontrollable hyperphagia associated with PWS. DRD2 antagonists are prescribed for treating schizophrenia, but these block dopamine signaling in all DRD2 expressing neurons and are associated with adverse side effects, including enhanced appetite and excessive weight gain. A GHSR1a antagonist of structural class that allosterically blocks dopamine/DRD2 action in GHSR1a:DRD2 expressing neurons would have no effect on neurons expressing DRD2 alone; therefore, the side effects of DRD2 antagonists would potentially be reduced thereby enhancing patient compliance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 252 | Front Behav Neurosci 2014 -1 8: 235 |
| PMID | 25071490 |
| Title | Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2. |
| Abstract | "schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 253 | Clin Schizophr Relat Psychoses 2014 Jun -1: 1-27 |
| PMID | 24951719 |
| Title | Genetic Variation of the Mu Opioid Receptor (OPRM1) and Dopamine D2 Receptor (DRD2) is Related to Smoking Differences in Patients with Schizophrenia but not Bipolar Disorder. |
| Abstract | It is not known why mentally ill persons smoke excessively. Inasmuch as endogenous opioid and dopaminergic systems are involved in smoking reinforcement, it is important to study mu opioid receptor (OPRM1) A118G (rs1799971), dopamine D2 receptor (DRD2) Taq1A (rs1800497) genotypes, and sex differences among patients with schizophrenia or bipolar disorder. Smokers and nonsmokers with schizophrenia (177) and bipolar disorder (113) were recruited and genotyped. They were classified into three groups: current smoker, former smoker, and never smoker by tobacco smoking status self-report. The number of cigarettes smoked per day was used as the major tobacco smoking parameter. In patients with schizophrenia, tobacco smoking prevalence was greater in males than in females as expected, but women had greater daily cigarette consumption (p<0.01). Subjects with schizophrenia who had the OPRM1 *G genotype smoked more cigarettes per day than the AA allele carriers with schizophrenia (p<0.05). DRD2 Taq1A genotype differences had no effect on the number of cigarettes smoked per day. However, female smokers with schizophrenia who were GG homozygous with the DRD2 receptor smoked more than the *A male smokers with schizophrenia (p<0.05). In bipolar patients, there were no OPRM1 and DRD2 Taq1A genotype differences in smoking status. There also were no sex differences for smoking behavior among the bipolar patients. The results of this study indicate that single nucleotide polymorphism (SNP) of the less functional mu opioid receptor increases tobacco smoking in patients with schizophrenia. Alteration of DRD2 receptor function also increased smoking behavior in females with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 254 | J. Biol. Chem. 2014 May 289: 13434-44 |
| PMID | 24675081 |
| Title | MicroRNA-9 and microRNA-326 regulate human dopamine D2 receptor expression, and the microRNA-mediated expression regulation is altered by a genetic variant. |
| Abstract | The human dopamine receptor D2 (DRD2) has been implicated in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Most antipsychotic drugs influence dopaminergic transmission through blocking dopamine receptors, primarily DRD2. We report here the post-transcriptional regulation of DRD2 expression by two brain-expressed microRNAs (miRs), miR-326 and miR-9, in an ex vivo mode, and show the relevance of miR-mediated DRD2 expression regulation in human dopaminergic neurons and in developing human brains. Both miRs targeted the 3'-UTR (untranslated region) of DRD2 in NT2 (neuron-committed teratocarcinoma, which endogenously expresses DRD2) and CHO (Chinese hamster ovary) cell lines, decreasing luciferase activity measured by a luciferase reporter gene assay. miR-326 overexpression reduced DRD2 mRNA and DRD2 receptor synthesis. Both antisense miR-326 and antisense miR-9 increased DRD2 protein abundance, suggesting an endogenous repression of DRD2 expression by both miRs. Furthermore, a genetic variant (rs1130354) within the DRD2 3'-UTR miR-targeting site interferes with miR-326-mediated repression of DRD2 expression. Finally, co-expression analysis identified an inverse correlation of DRD2 expression with both miR-326 and miR-9 in differentiating dopaminergic neurons derived from human induced pluripotent stem cells (iPSCs) and in developing human brain regions implicated in schizophrenia. Our study provides empirical evidence suggesting that miR-326 and miR-9 may regulate dopaminergic signaling, and miR-326 and miR-9 may be considered as potential drug targets for the treatment of disorders involving abnormal DRD2 function, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 255 | Med. Hypotheses 2014 May 82: 606-14 |
| PMID | 24636783 |
| Title | Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior. |
| Abstract | The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 256 | Neurosci. Lett. 2014 Mar 563: 123-8 |
| PMID | 24491429 |
| Title | Comprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin. |
| Abstract | Blonanserin is a second-generation antipsychotic drug for schizophrenia. The pharmacological actions of blonanserin are shown to be the antagonism of dopamine receptor 2 and serotonin receptors. However, its molecular mechanisms in brain cells have not been fully characterized. Accumulating evidence suggests that antipsychotic drugs and mood stabilizers show epigenetic effects on a wide range of genes in animal and cellular models. We performed genome-wide DNA methylation analysis targeting 479,814 CpG sites of cultured human neuroblastoma cells administered with blonanserin. We found that 3,057 CpG sites showed statistically significant changes in DNA methylation at two different doses of blonanserin (1.36 nM and 13.6 nM). These included hypermethylated CpG sites that were enriched in genes related to axonogenesis and cell morphogenesis involved in neuron differentiation. We also showed that the global effect on DNA methylome depends on the concentration of the drug. With a high dose of blonanserin, the overall methylation levels across all CpG sites significantly increased. These increases in DNA methylation were prominent in the CpG sites distant from promoter regions. We further examined DNA methylation changes in specific genes implicated for the actions of antipsychotic drugs, such as the dopamine receptor 2 (DRD2) gene and the serotonin receptor 2A (HTR2A) gene. We observed that CpG sites that were located within DRD2 and HTR2A genes were significantly hypermethylated by blonanserin. The DNA methylation changes induced by the treatment with blonanserin will be useful for understanding its pharmacological actions at the cellular level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 257 | Science 2014 Jun 344: 1178-82 |
| PMID | 24904170 |
| Title | Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. |
| Abstract | Auditory hallucinations in schizophrenia are alleviated by antipsychotic agents that inhibit D2 dopamine receptors (DRD2s). The defective neural circuits and mechanisms of their sensitivity to antipsychotics are unknown. We identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an aberrant elevation of DRD2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the DRD2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. This suggests that Dgcr8-microRNA-DRD2-dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 258 | Med. Hypotheses 2014 May 82: 606-14 |
| PMID | 24636783 |
| Title | Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior. |
| Abstract | The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 259 | Front Behav Neurosci 2014 -1 8: 235 |
| PMID | 25071490 |
| Title | Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2. |
| Abstract | "schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 260 | Front Behav Neurosci 2014 -1 8: 235 |
| PMID | 25071490 |
| Title | Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2. |
| Abstract | "schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 261 | Med. Hypotheses 2014 May 82: 606-14 |
| PMID | 24636783 |
| Title | Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior. |
| Abstract | The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 262 | Value Health 2015 Nov 18: A344 |
| PMID | 26531949 |
| Title | Cytogenetics And Dopamine Receptor (Drd2) Gene Polymorphism In Schizophrenia Patients. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 263 | J Clin Psychopharmacol 2015 Jun 35: 333-4 |
| PMID | 25871573 |
| Title | Influence of -141C Ins/Del Polymorphism in DRD2 Gene on Clinical Symptoms and Plasma Homovanillic Acid Levels in the Treatment of Schizophrenia With Aripiprazole. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 264 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Apr 168B: 224-8 |
| PMID | 25711927 |
| Title | DRD2 Ser311Cys polymorphism and risk of schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 265 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Apr 168B: 223 |
| PMID | 25711779 |
| Title | Response to "DRD2 Ser311Cys polymorphism and risk of schizophrenia". |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 266 | Mol. Psychiatry 2015 Aug 20: 951-8 |
| PMID | 25155879 |
| Title | Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats. |
| Abstract | Gpr88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinson's disease or schizophrenia (SZ). This study investigated the relevance of Gpr88 to SZ-associated behavior by knocking down Gpr88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of Gpr88 and of DRD2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically Gpr88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of Gpr88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for Gpr88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 267 | Neuropsychiatr Dis Treat 2015 -1 11: 1845-51 |
| PMID | 26251601 |
| Title | Genetic association between G protein-coupled receptor kinase 6/?-arrestin 2 and dopamine supersensitivity psychosis in schizophrenia. |
| Abstract | Dopamine supersensitivity psychosis (DSP), clinically characterized by unstable and severe psychosis or tardive dyskinesia and often categorized as treatment-resistant schizophrenia, is promoted by long-term antipsychotic treatment. An upregulation of the dopamine D2 receptor caused by antipsychotic(s) is involved in the development of DSP. The present study explored the potential roles of G protein-coupled receptor kinase 6 (GRK6) and ?-arrestin 2 (ARRB2) that are involved in the trafficking of DRD2 in patients with DSP. We conducted a genetic association study of GRK6/ARRB2 between the patients with DSP episodes [DSP(+) group: N=108] and the patients without DSP(-) episodes [DSP(-) group: N=169] from the total group of patients (N=333). Based on the patients' treatment history, a DSP episode was defined as withdrawal psychosis, developed tolerance to antipsychotic effect, and tardive dyskinesia (the remaining 56 patients were excluded due to insufficient information). The results revealed that none of the allelic or genotyping distributions of five single nucleotide polymorphisms (SNPs) of GRK6 and three SNPs of ARRB2 showed any significant difference between the DSP(+) and DSP(-) groups. The results suggest that the SNP analyses of these two molecules fail to classify patients into the potential clinical subtype of DSP(+) or DSP(-) group. However, since GRK6 and ARRB2 are surely involved in dopamine D2 receptor metabolism, further studies based on prospective observations of the onset of DSP under specific antipsychotic treatments are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 268 | 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 |
| 269 | Neuroscience 2015 Sep 304: 279-85 |
| PMID | 26192093 |
| Title | Prenatal stress induces vulnerability to nicotine addiction and alters D2 receptors' expression in the nucleus accumbens in adult rats. |
| Abstract | Prenatal stress (PS) can induce several long-lasting behavioral and molecular abnormalities in rats. It can also be considered as a risk factor for many psychiatric diseases like schizophrenia, depression or PTSD and predispose to addiction. In this study, we investigated the effect of prenatal stress on the reinforcing properties of nicotine in the CPP paradigm. Then, we examined the mRNA expression of the D2 dopaminergic receptors using the quantitative real-time PCR technique in the nucleus accumbens (NAcc). We found that prenatally stressed rats exhibited a greater place preference for the nicotine-paired compartment than the control rats. Moreover, we observed an overexpression of the DRD2 gene in adult offspring stressed in utero and a downregulation in the PS NIC group (PS rats treated with nicotine) compared with their control counterparts (C NIC). These data suggest that maternal stress can permanently alter the offspring's addictive behavior and D2 receptors' expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 270 | ACS Chem Neurosci 2015 Feb 6: 297-305 |
| PMID | 25393953 |
| Title | Loss of dopamine D2 receptors increases parvalbumin-positive interneurons in the anterior cingulate cortex. |
| Abstract | Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected. Interneuron distribution and number were not altered in the striatum or in the dopamine-poor somatosensory cortex. The changes were already present by postnatal day 14, indicating a developmental etiology. D2eGFP BAC transgenic mice demonstrated the presence of D2 receptor expression within a subset of parvalbumin-expressing cortical interneurons, suggesting the possibility of a direct cellular mechanism through which D2 receptor stimulation regulates interneuron differentiation or survival. D2 receptor knockout mice also exhibited decreased depressive-like behavior compared with wild-type controls in the tail suspension test. These data indicate that dopamine signaling modulates interneuron number and emotional behavior and that developmental D2 receptor loss or blockade could reveal a potential mechanism for the prodromal basis of neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 271 | 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 |
| 272 | Mol. Psychiatry 2015 Jul 20: 820-6 |
| PMID | 25869805 |
| Title | Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic. |
| Abstract | The Psychiatric Genomics Consortium-schizophrenia Workgroup (PGC-SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12-15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC-SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC-SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC-SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 273 | 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 |
| 274 | Int J Mol Sci 2015 -1 16: 30144-63 |
| PMID | 26694375 |
| Title | Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia. |
| Abstract | Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%-30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 275 | Int J Mol Sci 2015 -1 16: 26677-86 |
| PMID | 26561806 |
| Title | The mRNA Expression Status of Dopamine Receptor D2, Dopamine Receptor D3 and DARPP-32 in T Lymphocytes of Patients with Early Psychosis. |
| Abstract | Peripheral blood lymphocytes are an attractive tool because there is accumulating evidence indicating that lymphocytes may be utilized as a biomarker in the field of psychiatric study as they could reveal the condition of cells distributed in the brain. Here, we measured the mRNA expression status of dopamine receptor D2 (DRD2), DRD3, and dopamine and cyclic adenosine 3',5'-monophosphate regulated phosphoprotein-32 (DARPP-32) in T lymphocytes of patients with early psychosis by quantitative real-time polymerase chain reaction (q-PCR) and explored the relationships between their mRNA levels and the psychopathological status of patients. The present study demonstrated that the mRNA expression levels of DRD3 in T lymphocytes were significantly different among controls, and in patients with psychotic disorder not otherwise specified (NOS) and schizophrenia/schizophreniform disorder. However, no significant differences in mRNA expression levels of DRD2 and DARPP-32 were found among the three groups. We found a significant positive correlation between the DRD2 mRNA level and the score of the excited factor of the Positive and Negative Syndrome Scale (PANSS) in patients with schizophrenia/schizophreniform disorder. These findings suggest that DRD3 mRNA levels may serve as a potential diagnostic biomarker differentiating patients with early psychosis from controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 276 | Mol. Psychiatry 2015 Sep -1: -1 |
| PMID | 26347318 |
| Title | A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples. |
| Abstract | The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.Molecular Psychiatry advance online publication, 8 September 2015; doi:10.1038/mp.2015.137. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 277 | Schizophr Bull 2015 Nov 41: 1248-55 |
| PMID | 26320194 |
| Title | Association of a Schizophrenia Risk Variant at the DRD2 Locus With Antipsychotic Treatment Response in First-Episode Psychosis. |
| Abstract | Findings from the Psychiatric Genomics Consortium genome-wide association study (GWAS) showed that variation at the DRD2 locus is associated with schizophrenia risk. However, the functional significance of rs2514218, the top DRD2 single nucleotide polymorphism in the GWAS, is unknown. Dopamine D2 receptor binding is a common mechanism of action for all antipsychotic drugs, and DRD2 variants were related to antipsychotic response in previous studies. The present study examined whether rs2514218 genotype could predict antipsychotic response, including efficacy and adverse events, in a cohort of patients with first episode of psychosis treated with either risperidone or aripiprazole for 12 weeks. Subjects were genotyped using the Illumina Infinium HumanOmniExpressExome array platform. After standard quality control, data from 100 subjects (49 randomly assigned to treatment with aripiprazole and 51 assigned to risperidone) was available for analysis. Subjects were assessed for psychotic symptomatology and medication-related adverse events weekly for 4 weeks, then biweekly for 8 weeks. Linear mixed model analysis revealed that the homozygotes for the risk (C) allele at rs2514218 had significantly greater reduction in positive symptoms during 12 weeks of treatment compared to the T allele carriers. In the aripiprazole group, C/C homozygotes also reported more akathisia than the T allele carriers, while in the risperidone group, male T allele carriers demonstrated greater prolactin elevations compared to male C/C homozygotes. These findings suggest that the schizophrenia risk variant at the DRD2 locus (or another variant in close proximity) is associated with observable differences in response to treatments which reduce striatal dopamine signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 278 | PeerJ 2015 -1 3: e1149 |
| PMID | 26290802 |
| Title | Selection in the dopamine receptor 2 gene: a candidate SNP study. |
| Abstract | Dopamine is a major neurotransmitter in the human brain and is associated with various diseases. schizophrenia, for example, is treated by blocking the dopamine receptors type 2. Shaner, Miller & Mintz (2004) stated that schizophrenia was the low fitness variant of a highly variable mental trait. We therefore explore whether the dopamine receptor 2 gene (DRD2) underwent any selection processes. We acquired genotype data of the 1,000 Genomes project (phase I), which contains 1,093 individuals from 14 populations. We included single nucleotide polymorphisms (SNPs) with two minor allele frequencies (MAFs) in the analysis: MAF over 0.05 and over 0.01. This is equivalent to 151 SNPs (MAF > 0.05) and 246 SNPs (MAF > 0.01) for DRD2. We used two different approaches (an outlier approach and a Bayesian approach) to detect loci under selection. The combined results of both approaches yielded nine (MAF > 0.05) and two candidate SNPs (MAF > 0.01), under balancing selection. We also found weak signs for directional selection on DRD2, but in our opinion these were too weak to draw any final conclusions on directional selection in DRD2. All candidates for balancing selection are in the intronic region of the gene and only one (rs12574471) has been mentioned in the literature. Two of our candidate SNPs are located in specific regions of the gene: rs80215768 lies within a promoter flanking region and rs74751335 lies within a transcription factor binding site. We strongly encourage research on our candidate SNPs and their possible effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 279 | Schizophr Bull 2015 Sep 41: 1171-82 |
| PMID | 25829376 |
| Title | Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis. |
| Abstract | Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ? .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ? .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 280 | J Clin Psychopharmacol 2015 Apr 35: 158-62 |
| PMID | 25679126 |
| Title | DRD2 genotypic and haplotype variation is associated with improvements in negative symptoms after 6 weeks' amisulpride treatment. |
| Abstract | The aim of this study was to identify the association between the rs1079597 and rs1800497 genetic polymorphisms of the gene encoding the dopamine D2 receptor (DRD2) protein and the treatment response to the selective dopamine receptor antagonist amisulpride. After 6 weeks of treatment with amisulpride, 125 schizophrenia patients were interviewed based on the Positive and Negative Syndrome Scale and the Clinical Global Impression-Severity Scale. Genotyping for rs1079597 and rs1800497 was performed using the TaqMan single nucleotide polymorphism genotyping assay. There were significant differences in the genotype frequency of the recessive model (? = 5.73, P = 0.017) and allele frequency (? = 5.16, P = 0.023) of rs1079597 between the responders and nonresponders based on the Positive and Negative Syndrome Scale negative symptoms scores. There was no significant finding in this regard for the rs1800497 polymorphism. The T-C and C-C haplotype of rs1079597-rs1800497 were associated with the negative symptom treatment response to amisulpride after permutation test. To the best of our knowledge, this is the first report of the positive finding in the association study between rs1079597 polymorphism and the treatment response to amisulpride in schizophrenic patients. A larger scale study involving more single nucleotide polymorphisms of DRD2 will progress the research into the pharmacogenetics of the treatment response to amisulpride. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 281 | Neuropsychopharmacology 2015 Jun 40: 1600-8 |
| PMID | 25563748 |
| Title | Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics. |
| Abstract | Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 282 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Jan 168B: 1-13 |
| PMID | 25504812 |
| Title | Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: a meta-analysis. |
| Abstract | The role of dopamine D2 receptor (DRD2) polymorphisms in schizophrenia remains controversial. We performed a meta-analysis to determine whether DRD2 polymorphisms influence the risk of schizophrenia and examined the relationship between rs1799732, rs1801028, and rs1800rs028 an23381d rs1800497 genetic variants and the etiology of schizophrenia. Relevant case-control studies were retrieved by database searches and selected according to established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, and cumulative meta-analysis were performed. A total of 76 studies with 16096 cases and 18965 controls were included. Specifically, 24 studies with 6075 cases and 6643 controls involved rs1799732, 36 studies with 8043 cases and 10194 controls involved rs1801028 and 16 studies with 1978 cases and 2128 controls involved rs1800497. No significant associations were observed between rs1799732 and rs1800rs732 and rs1800497 and schizophrenia. The rs1801028 locus was associated with schizophrenia, with a pooled OR of 1.221 (95% CI = 1.037-1.438, P = 0.016). This meta-analysis indicates that the rs1801028 locus may be associated with schizophrenia. These data provide possible references for future case-control studies related to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 283 | Biochem. Pharmacol. 2015 Jan 93: 85-91 |
| PMID | 25449598 |
| Title | New functional activity of aripiprazole revealed: Robust antagonism of D2 dopamine receptor-stimulated G?? signaling. |
| Abstract | The dopamine D2 receptor (DRD2) is a G protein-coupled receptor (GPCR) that is generally considered to be a primary target in the treatment of schizophrenia. First generation antipsychotic drugs (e.g. haloperidol) are antagonists of the DRD2, while second generation antipsychotic drugs (e.g. olanzapine) antagonize DRD2 and 5HT2A receptors. Notably, both these classes of drugs may cause side effects associated with D2 receptor antagonism (e.g. hyperprolactemia and extrapyramidal symptoms). The novel, "third generation" antipsychotic drug, aripiprazole is also used to treat schizophrenia, with the remarkable advantage that its tendency to cause extrapyramidal symptoms is minimal. Aripiprazole is considered a partial agonist of the DRD2, but it also has partial agonist/antagonist activity for other GPCRs. Further, aripiprazole has been reported to have a unique activity profile in functional assays with the DRD2. In the present study the molecular pharmacology of aripiprazole was further examined in HEK cell models stably expressing the DRD2 and specific isoforms of adenylyl cyclase to assess functional responses of G? and G?? subunits. Additional studies examined the activity of aripiprazole in DRD2-mediated heterologous sensitization of adenylyl cyclase and cell-based dynamic mass redistribution (DMR). Aripiprazole displayed a unique functional profile for modulation of G proteins, being a partial agonist for G?i/o and a robust antagonist for G?? signaling. Additionally, aripiprazole was a weak partial agonist for both heterologous sensitization and dynamic mass redistribution. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 284 | 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 |
| 285 | J Clin Psychopharmacol 2015 Apr 35: 158-62 |
| PMID | 25679126 |
| Title | DRD2 genotypic and haplotype variation is associated with improvements in negative symptoms after 6 weeks' amisulpride treatment. |
| Abstract | The aim of this study was to identify the association between the rs1079597 and rs1800497 genetic polymorphisms of the gene encoding the dopamine D2 receptor (DRD2) protein and the treatment response to the selective dopamine receptor antagonist amisulpride. After 6 weeks of treatment with amisulpride, 125 schizophrenia patients were interviewed based on the Positive and Negative Syndrome Scale and the Clinical Global Impression-Severity Scale. Genotyping for rs1079597 and rs1800497 was performed using the TaqMan single nucleotide polymorphism genotyping assay. There were significant differences in the genotype frequency of the recessive model (? = 5.73, P = 0.017) and allele frequency (? = 5.16, P = 0.023) of rs1079597 between the responders and nonresponders based on the Positive and Negative Syndrome Scale negative symptoms scores. There was no significant finding in this regard for the rs1800497 polymorphism. The T-C and C-C haplotype of rs1079597-rs1800497 were associated with the negative symptom treatment response to amisulpride after permutation test. To the best of our knowledge, this is the first report of the positive finding in the association study between rs1079597 polymorphism and the treatment response to amisulpride in schizophrenic patients. A larger scale study involving more single nucleotide polymorphisms of DRD2 will progress the research into the pharmacogenetics of the treatment response to amisulpride. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 286 | Neurosci. Lett. 2015 Oct 606: 60-5 |
| PMID | 26297122 |
| Title | Studies on the regulatory effect of Peony-Glycyrrhiza Decoction on prolactin hyperactivity and underlying mechanism in hyperprolactinemia rat model. |
| Abstract | Clinical trials have demonstrated the beneficial effects of Peony-Glycyrrhiza Decoction (PGD) in alleviating antipsychotic-induced hyperprolactinemia (hyperPRL) in schizophrenic patients. In previous experiment, PGD suppressed prolactin (PRL) level in MMQ cells, involving modulating the expression of D2 receptor (DRD2) and dopamine transporter (DAT). In the present study, hyperPRL female rat model induced by dopamine blocker metoclopramide (MCP) was applied to further confirm the anti-hyperpPRL activity of PGD and underlying mechanism. In MCP-induced hyperPRL rats, the elevated serum PRL level was significantly suppressed by either PGD (2.5-10 g/kg) or bromocriptine (BMT) (0.6 mg/kg) administration for 14 days. However, in MCP-induced rats, only PGD restored the under-expressed serum progesterone (P) to control level. Both PGD and BMT administration restore the under-expression of DRD2, DAT and TH resulted from MCP in pituitary gland and hypothalamus. Compared to untreated group, hyperPRL animals had a marked reduction on DRD2 and DAT expression in the arcuate nucleus. PGD (10 g/kg) and BMT (0.6 mg/kg) treatment significant reversed the expression of DRD2 and DAT. Collectively, the anti-hyperPRL activity of PGD associates with the modulation of dopaminergic neuronal system and the restoration of serum progesterone level. Our finding supports PGD as an effective agent against hyperPRL. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 287 | Schizophr Bull 2015 Sep 41: 1171-82 |
| PMID | 25829376 |
| Title | Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis. |
| Abstract | Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ? .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ? .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 288 | Schizophr Bull 2015 Sep 41: 1171-82 |
| PMID | 25829376 |
| Title | Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis. |
| Abstract | Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ? .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ? .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 289 | Schizophr Bull 2016 May -1: -1 |
| PMID | 27217270 |
| Title | Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. |
| Abstract | Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (?7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 290 | Neurosci. Lett. 2016 Apr 619: 126-30 |
| PMID | 26957229 |
| Title | Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis. |
| Abstract | Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 291 | Pharmacogenomics 2016 -1 17: 103-9 |
| PMID | 26666695 |
| Title | Preliminary evidence for association of genome-wide significant DRD2 schizophrenia risk variant with clozapine response. |
| Abstract | The recent Psychiatric Genomics Consortium genome-wide association study identified an SNP, rs2514218, located 47kb upstream of the DRD2 gene to be associated with risk for schizophrenia (p = 2.75e-11). Since all antipsychotics bind to dopamine D2 receptors, we examined rs2514218 in relation to response to antipsychotic treatment. We investigated the SNP in relation to treatment response in a prospective study consisting of 208 patients (151 Caucasians, 42 African-Americans and 15 others) treated with clozapine for 6 months. rs2514218 was associated with total score change in the brief psychiatric rating scale under an additive model (pcorr= 0.033). Our finding provides evidence for rs2514218 association with antipsychotic response, but further replication is required before firm conclusions can be drawn. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 292 | Biochimie 2016 Apr 123: 52-64 |
| PMID | 26805384 |
| Title | Investigating the structural impact of S311C mutation in DRD2 receptor by molecular dynamics & docking studies. |
| Abstract | Dopamine receptors (DR) are neuronal cell surface proteins that mediate the action of neurotransmitter dopamine in brain. Dopamine receptor D2 (DRD2) that belongs to G-protein coupled receptors (GPCR) family is a major therapeutic target for of various neurological and psychiatric disorders in human. The third inter cellular loop (ICL3) in DRD2 is essential for coupling G proteins and several signaling scaffold proteins. A mutation in ICL3 can interfere with this binding interface, thereby altering the DRD2 signaling. In this study we have examined the deleterious effect of serine to cysteine mutation at position 311 (S311C) in the ICL3 region that is implicated in diseases like schizophrenia and alcoholism. An in silico structure modeling approach was employed to determine the wild type (WT) and mutant S311C structures of DRD2, scaffold proteins - G?i/o and NEB2. Protein-ligand docking protocol was exercised to predict the interactions of natural agonist dopamine with both the WT and mutant structures of DRD2. Besides, atomistic molecular dynamics (MD) simulations were performed to provide insights into essential dynamics of the systems-unbound and dopamine bound DRD2 (WT and mutant) and three independent simulations for G?i, G?o and NEB2 systems. To provide information on intra-molecular arrangement of the structures, a comprehensive residue interactions network of both dopamine bound WT and mutant DRD2 protein were studied. We also employed a protein-protein docking strategy to find the interactions of scaffold proteins - G?i/o and NEB2 with both dopamine bound WT and mutant structures of DRD2. We observed a marginal effect of the mutation in dopamine binding mechanism on the trajectories analyzed. However, we noticed a significant structural alteration of the mutant receptor which affects G?i/o and NEB2 binding that can be causal for malfunctioning in cAMP-dependent signaling and Ca(+) homeostasis in the brain dopaminergic system leading to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 293 | 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 |
| 294 | Can J Psychiatry 2016 May 61: 291-7 |
| PMID | 27254804 |
| Title | Dopamine 2 Receptor Genes Are Associated with Raised Blood Glucose in Schizophrenia. |
| Abstract | Type 2 diabetes is commonly found in schizophrenia and is an important contributor to mortality and morbidity in this condition. Dopamine has been implicated in the aetiology of both diabetes and schizophrenia. It is possible that both disorders share a common genetic susceptibility. In a cross-sectional study, we examined 2 dopamine D2 receptor (DRD2) single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia (C939 T, rs6275 and C957 T, rs6277) along with fasting blood glucose and body mass index (BMI) in 207 antipsychotic-treated patients with schizophrenia. All participants met DSM-IV criteria for schizophrenia, and those with other psychiatric disorders were excluded. Analysis of covariance was used to compare fasting glucose results by DRD2 genotypes, after controlling for known confounds. For significant associations, follow-up Bonferroni post hoc tests examined differences in fasting glucose levels between genotypes. Specific comparisons were also made using analysis of variance and chi-square (Fisher's exact test). The 2 DRD2 risk genotypes were associated with significant increases in blood glucose, after controlling for BMI, age, sex, dosage and type of antipsychotic medication, number of hospitalisations, and negative symptoms (rs6275, F(2, 182) = 5.901, P = 0.003; rs6277 SNP, F(2, 178) = 3.483, P = 0.033). These findings support the involvement of DRD2 not only in schizophrenia but also in elevated levels of blood glucose commonly found in antipsychotic-treated patients with schizophrenia. Our data support the notion that diabetes may not merely be a comorbid condition but could be fundamentally associated with the pathogenesis of schizophrenia itself. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 295 | Synapse 2016 May -1: -1 |
| PMID | 27241797 |
| Title | Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status. |
| Abstract | In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5-12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. This article is protected by copyright. All rights reserved. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 296 | Curr Opin Psychiatry 2016 Jul 29: 236-41 |
| PMID | 27175554 |
| Title | Psychosis induced by amphetamines. |
| Abstract | The study reviews publications on the use of methamphetamine and amphetamine in relation to psychotic symptoms, substance-induced psychosis, and primary psychosis published between July 2014 and December 2015. The databases MEDLINE, Embase, and PsycINFO were searched using the terms 'amphetamine psychosis' and 'methamphetamine psychosis' for the time period 1 July 2014 to 31 December 2015. There were 37 studies published on the subject during this time period. Risk factors for psychotic symptoms, substance-induced psychosis, and primary psychosis included patterns of drug use, but results also pointed to the importance of nondrug-related vulnerability. Cognitive impairment is associated with both amphetamine use and psychosis, and the impairment among those with amphetamine-induced psychosis resembles that of schizophrenia. At the neuronal level, GABAergic mechanisms may offer some understanding about the association between stimulant use and psychosis. Several different types of antipsychotic medication are effective for treating agitation and psychosis, but drugs with high DRD2 blockade should be used with caution. Some novel treatments are described, but are not sufficiently repeated to be recommended. During the past 18 months, studies have been published that cover risk factors, neuronal mechanisms, and treatment. These recent results do not differ from previous understandings, but the role of cognition and GABAergic dysfunction should be further investigated, and knowledge about resilience factors is still scarce. Also, a clearer evidence base for medical treatment of psychosis with concurrent amphetamine use is warranted. VIDEO ABSTRACT. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 297 | Psychiatry Res 2016 Jun 240: 209-13 |
| PMID | 27111215 |
| Title | Relation between serum prolactin levels and antipsychotic response to risperidone in patients with schizophrenia. |
| Abstract | Hyperprolactinemia is commonly seen in patients with schizophrenia on risperidone. Dopamine receptor blockade plays a major role in risperidone induced hyperprolactinemia. However, limited studies are available with inconsistent results on antipsychotic response to risperidone and prolactin elevation. Therefore, we aimed to study the change in serum prolactin levels and response to risperidone and to test the association between DRD2 genetic variants and prolactin levels in schizophrenic patients treated with risperidone. A prospective study comprising of 102 patients with schizophrenia were recruited. Prolactin levels and Positive and Negative Syndrome Scale (PANSS) score were recorded at baseline and after four weeks of risperidone treatment. Prolactin concentrations were measured by standard method Advia-Centaur® Chemiluminescence immuno assay method. Taq1A DRD2 genotyping was performed by qRT-PCR. The mean±SD prolactin levels (ng/ml) were increased after four weeks of treatment in both responders (males 21.66±15.15 to 41.63±18.73; p<0.01 females 51.92±40.89 to 122.35±52.16; p<0.01) and non-responders group (males 23.89±14.85 to 37.45±13.5; p<0.01 females 39.25±26.94 to 91.13±54.31; p<0.01). Patients with increased prolactin concentration were 4.6 fold higher in responders (OR 4.60; 95%CI 1.376-15.389; p-value 0.01) compared to non-responders. Ninety-six patients were genotyped for Taq1A DRD2 gene (AA=9, AG=46, GG=41) and found no association (p=0.6) between genetic variants and response to risperidone. Patients were showing more than 20% increase in prolactin levels had a better chance of responding to risperidone therapy. Taq1A DRD2 gene did not show any association with prolactin elevation and response to risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 298 | Schizophr Bull 2016 May 42: 843-50 |
| PMID | 26598739 |
| Title | DRD2 Schizophrenia-Risk Allele Is Associated With Impaired Striatal Functioning in Unaffected Siblings of Schizophrenia Patients. |
| Abstract | A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n= 21) and noncarriers (n= 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 299 | Hum. Mol. Genet. 2016 Jan 25: 167-79 |
| PMID | 26464489 |
| Title | Common variants in DRD2 are associated with sleep duration: the CARe consortium. |
| Abstract | Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ?50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |
| 300 | Psychiatry Res 2016 Jun 240: 209-13 |
| PMID | 27111215 |
| Title | Relation between serum prolactin levels and antipsychotic response to risperidone in patients with schizophrenia. |
| Abstract | Hyperprolactinemia is commonly seen in patients with schizophrenia on risperidone. Dopamine receptor blockade plays a major role in risperidone induced hyperprolactinemia. However, limited studies are available with inconsistent results on antipsychotic response to risperidone and prolactin elevation. Therefore, we aimed to study the change in serum prolactin levels and response to risperidone and to test the association between DRD2 genetic variants and prolactin levels in schizophrenic patients treated with risperidone. A prospective study comprising of 102 patients with schizophrenia were recruited. Prolactin levels and Positive and Negative Syndrome Scale (PANSS) score were recorded at baseline and after four weeks of risperidone treatment. Prolactin concentrations were measured by standard method Advia-Centaur® Chemiluminescence immuno assay method. Taq1A DRD2 genotyping was performed by qRT-PCR. The mean±SD prolactin levels (ng/ml) were increased after four weeks of treatment in both responders (males 21.66±15.15 to 41.63±18.73; p<0.01 females 51.92±40.89 to 122.35±52.16; p<0.01) and non-responders group (males 23.89±14.85 to 37.45±13.5; p<0.01 females 39.25±26.94 to 91.13±54.31; p<0.01). Patients with increased prolactin concentration were 4.6 fold higher in responders (OR 4.60; 95%CI 1.376-15.389; p-value 0.01) compared to non-responders. Ninety-six patients were genotyped for Taq1A DRD2 gene (AA=9, AG=46, GG=41) and found no association (p=0.6) between genetic variants and response to risperidone. Patients were showing more than 20% increase in prolactin levels had a better chance of responding to risperidone therapy. Taq1A DRD2 gene did not show any association with prolactin elevation and response to risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal |