1Neuropsychopharmacology 2000 Jul 23: 1-12
PMID10869881
TitleThe genes for major psychosis: aberrant sequence or regulation?
AbstractA number of recent clinical and molecular observations in major psychosis indicate that epigenetic factors may be operational in the origin of major mental illness. This article further develops the idea that epigenetic factors may play an etiopathogenic role in schizophrenia and bipolar affective disorder. The putative role of epigenetic factors is shown by the epigenetic interpretation of genetic association studies of the genes for serotonin 2A (HTR2A) and the dopamine D3 (DRD3) receptors in schizophrenia. The idea of epigenetic polymorphism of genetic alleles is introduced, and it is argued that epigenetic variation may explain a number of controversial and unclear findings in allelic and genotypic association studies of HTR2A and DRD3. In linkage analyses of multiplex families with bipolar affective disorder (BPAD), different loci on chromosome 18 indicated co-segregation of alleles of one parental sex with the disease phenotype, and this finding implies that the epigenetic mechanism of genomic imprinting may be involved. Evidence for genomic imprinting provides the background for epigenetic cloning of BPAD risk factors by searching for differentially modified genes on chromosome 18. Finally, epigenetic studies could be relevant to the better understanding of the molecular action of antipsychotic medications. In addition to this, if epimutations are detected in major psychosis, epigenetic treatment directed at correction of epigenetic status of a specific brain gene may eventually be developed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
2Eur. J. Pharmacol. 2000 Dec 410: 165-181
PMID11134668
TitlePharmacogenetics and the serotonin system: initial studies and future directions.
AbstractSerotonin (5-hydroxytryptamine, 5-HT) appears to play a role in the pathophysiology of a range of neuropsychiatric disorders, and serotonergic agents are of central importance in neuropharmacology. Genes encoding various components of the 5-HT system are being studied as risk factors in depression, schizophrenia, obsessive-compulsive disorder, aggression, alcoholism, and autism. Recently, pharmacogenetic research has begun to examine possible genetic influences on therapeutic response to drugs affecting the serotonin system. Genes regulating the synthesis (TPH), storage (VMAT2), membrane uptake (HTT), and metabolism (MAOA) of 5-HT, as well as a number of 5-HT receptors (HTR1A, HTR1B, HTR2A, HTR2C, and HTR5A), have been studied and this initial research is reviewed here. After a brief introduction to serotonin neurobiology and a general discussion of appropriate genetic methodology, each of the major 5-HT-related genes and their encoded proteins are reviewed in turn. For each gene, relevant polymorphisms and research on functional variants are discussed; following brief reviews of the disorder or trait association and linkage studies, pharmacogenetic studies performed to date are covered. The critical and manifold roles of the serotonin system, the great abundance of targets within the system, the wide range of serotonergic agents-available and in development-and the promising preliminary results suggest that the serotonin system offers a particularly rich area for pharmacogenetic research.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
3Genetika 2001 Apr 37: 545-8
PMID11421130
Title[Serotonin type 2a (5-HTR2A) receptor gene polymorphism and personality traits in patients with endogenous psychoses].
AbstractGenetic polymorphism of the serotonin receptor (5-HTR2A) gene has been reported to be associated with the expression of clinical signs characteristic of major psychoses, including schizophrenia and affective disorders. In this study, personality traits of patients with these diseases and the associations of these traits with 5-HTR2A allelic polymorphisms were studied. It was demonstrated that schizophrenic and affective patients with the 2/2 genotype of serotonin receptor had lower scores on the anxiety scale and on the anxiety-related hypochondriasis and neuroticism scales than subjects with the 1/1 and 1/2 genotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
4Genetika 2001 Apr 37: 545-8
PMID11421130
Title[Serotonin type 2a (5-HTR2A) receptor gene polymorphism and personality traits in patients with endogenous psychoses].
AbstractGenetic polymorphism of the serotonin receptor (5-HTR2A) gene has been reported to be associated with the expression of clinical signs characteristic of major psychoses, including schizophrenia and affective disorders. In this study, personality traits of patients with these diseases and the associations of these traits with 5-HTR2A allelic polymorphisms were studied. It was demonstrated that schizophrenic and affective patients with the 2/2 genotype of serotonin receptor had lower scores on the anxiety scale and on the anxiety-related hypochondriasis and neuroticism scales than subjects with the 1/1 and 1/2 genotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
5Zh Nevrol Psikhiatr Im S S Korsakova 2001 -1 101: 48-50
PMID11490436
Title[Molecular genetic polymorphism of the genes of neurotransmitter systems in schizophrenics with early manifestation of the disease].
AbstractMolecular-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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
6Zh Nevrol Psikhiatr Im S S Korsakova 2001 -1 101: 48-50
PMID11490436
Title[Molecular genetic polymorphism of the genes of neurotransmitter systems in schizophrenics with early manifestation of the disease].
AbstractMolecular-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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
7Mol. Psychiatry 2001 Mar 6: 230-4
PMID11317228
TitleLack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia.
AbstractTardive dyskinesia (TD) is a disabling neurological side effect associated with long-term treatment with typical antipsychotics. Family studies and animal models lend evidence for hereditary predisposition to TD. The newer atypical antipsychotics pose a minimal risk for TD which is in part attributed to their ability to block the serotonin-2A (5-HT(2A)) receptor. 5-HT(2A) receptors were also identified in the basal ganglia; a brain region that plays a critical role in antipsychotic-induced movement disorders. We tested the significance of variation in the 5-HT(2A) receptor gene (HTR2A) in relation to the TD phenotype. Three polymorphisms in HTR2A, one silent (C102T), one that alters the amino acid sequence (his452tyr) and one in the promoter region (A-1437G) were investigated in 136 patients refractory or intolerant to treatment with typical antipsychotics and with a DSM-IIIR diagnosis of schizophrenia. We did not find any significant difference in allele, genotype or haplotype frequencies of polymorphisms in HTR2A among patients with or without TD (P > 0.05). Further analysis using the ANCOVA statistic with a continuous measure of the TD phenotype (Abnormal Involuntary Movement Scale (AIMS) score) found that the AIMS scores were not significantly influenced by HTR2A polymorphisms, despite controlling for potential confounders such as age, gender and ethnicity (P > 0.05). Theoretically, central serotonergic function can be subject to genetic control at various other mechanistic levels including the rate of serotonin synthesis (tryptophane hydroxylase gene), release, reuptake (serotonin transporter gene) and degradation (monoamine oxidase gene). Analyses of these other serotonergic genes are indicated. In summary, polymorphisms in HTR2A do not appear to influence the risk for TD. Further studies evaluating in tandem multiple candidate genes relevant for the serotonergic system are warranted to dissect the genetic basis of the complex TD phenotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
8Mol. Psychiatry 2001 Mar 6: 225-9
PMID11317227
TitleAssociation between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia.
AbstractTardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.(1) Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.(2) We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility--T102C(3) and his452tyr(4) in the coding region and A-1438G(5) in the promoter--in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. There was a significant excess of 102C and -1438G alleles (62.7%) in the SCZ-TD-Y patients compared to SCZ-TD-N patients (41.1%) and controls (45.9%; chi(2) = 12.8, df = 2, P = 0.002; SCZ-TD-Y vs SCZ-TD-N, chi(2) = 11.4, df = 1, P = 0.0008, OR 2.41, 95% CI 1.43-3.99) and of 102CC and -1438GG genotypes (SCZ-TD-Y 42.4%, SCZ-TD-N, 16.1%, controls 20.8%, chi(2) = 13.3, df = 4, P = 0.01). The 102CC and the -1438GG genotypes were associated with significantly higher AIMS trunk dyskinesia scores (F = 3.9; df = 2, 116; P = 0.02) and more incapacitation (F = 5.0; df = 2, 115; P = 0.006). The his452tyr polymorphism showed no association with TD. These findings suggest that the 5-HT2A receptor gene is significantly associated with susceptibility to TD in patients with chronic schizophrenia. Previously reported association of the T102C and A-1438G polymorphisms with schizophrenia(6) may reflect association of a sub-group of patients with a susceptibility to abnormal involuntary movements related to antipsychotic drug exposure.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
9Cell. Mol. Life Sci. 2002 Feb 59: 331-48
PMID11915947
TitleRecent advances in the genetics of schizophrenia.
AbstractThe genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
10Zh Nevrol Psikhiatr Im S S Korsakova 2003 -1 103: 53-7
PMID14681967
Title[Polymorphism of serotonin receptor gene 5-HTR2A and schizotypic traits in mentally healthy subjects].
AbstractSerotonin receptor type 2 (5-HTR2A) polymorphism was consistently reported to be related to schizophrenia and some clinical presentations of the disease. The present study aimed at searching for association between 5-HTR2A polymorphism and schizotypic personality traits being considered as recognized phenotype predisposing to schizophrenia. Relationship between these features measured by SPQ-74 and two 5-HTR2A polymorphic loci has been studied in mentally healthy community sample (n = 64). Significant difference was found between AG and GG genotype carriers on No-close-friends scale (t = 2.3; p = 0.03), with GG scoring higher on this item. Also, a trend towards higher scores on this scale (p = 0.08) was observed in women, but not in men, with A2A2 genotype. To a certain extent, the results confirm a hypothesis articulated in the study of G-allele and A2-allele relation to interpersonal relationship factor of SPQ-74.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
11Zh Nevrol Psikhiatr Im S S Korsakova 2003 -1 103: 43-6
PMID12830506
Title[A-1438-G serotonin receptor type 2A (5-HTR2A) gene polymorphism in patients in patients with schizophrenia].
AbstractA-1438-G 5-HTR2A gene polymorphism is known to be related to some clinical presentations of endogenous psychoses, in particular, of schizophrenia. The present study aim was to study association between clinical appearances of schizophrenia and A-1438-G allelic polymorphism. Alleles (A and G) and genotypes (AA, AG and GG) distribution did not significantly differ between patients and control groups. No association has been found between the genotypes and clinical characteristics of the patients, such as age at disease onset, age at psychosis manifestation, as well as positive, negative and general psychopathological symptoms severity measured by PANSS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
12Acta Neuropsychiatr 2003 Jun 15: 129-32
PMID26983355
TitleThe serotonin-2A receptor polymorphism and clinical symptoms in mood disorders, schizophrenia and alcohol dependence in Japan.
AbstractIn the past, there have been many epidemiological and genetic studies of mood disorders, schizophrenia, and alcohol dependence, and in this study, the human serotonin 2A receptor (5-HTR2A) polymorphism was examined in 80 patients with mood disorders, 50 patients with schizophrenia and 41 patients with alcohol dependence. 5-HTR is related to affectivity, regulation, and pharmacologic effects of antidepressant, anti-anxiety and antipsychotic medications. The polymorphism in 5-HTR2A (102T/C, -1438 A/G) was identified by the polymerase chain reaction (PCR), followed by restriction fragment length polymorphism (RFLP). The results suggest that 5-HTR2A (102T/C, -1438G/A) polymorphism might not be associated with susceptibility to schizophrenia or mood disorders, and it might not be a risk factor contributing to alcohol dependency. We found that the 102T/C polymorphism was in linkage disequilibrium with the -1438G/A polymorphism in psychosis (mood disorder, schizophrenia, and alcohol dependence) and in health controls. Further studies are needed to determine whether or not the novel serotonin receptor (5-HTR) polymorphism reflects the pathogenesis of schizophrenia, mood disorders, and alcohol dependence.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
13Eur. J. Pharmacol. 2003 Nov 480: 177-84
PMID14623361
TitleThe genetics of schizophrenia: glutamate not dopamine?
AbstractThe major targets of current drugs used in mental health, such as neurotransmitter receptors and transporters, are based on serendipitous findings from several decades ago, and there is currently a severe drought of new drug targets. There is a pressing need for novel drugs, and much hope has been placed on the use of molecular genetics to help define them. However, despite evidence for a genetic basis to schizophrenia stretching back for over a century, and a heritability of about 80%, the identification of susceptibility genes has been an uphill struggle. Candidate gene studies, which have generally focussed on obvious candidates from the dopamine and serotonin systems, as well as genes involved in brain development, have not generally been successful, although meta-analysis indicates that the dopamine D3 receptor gene (DRD3) and the serotonin receptor gene type 2A (HTR2A) may have a very small influence on risk. Linkage analysis has provided robust evidence of genetic loci, for example, on chromosomes 8p, 13q and 22q, and also implies shared genetic aetiology with bipolar disorder. The identification of these loci together with advances in genetic technology, especially the characterisation of polymorphisms, the understanding of haplotypes and the development of statistical methods, has lead to the identification of several plausible susceptibility genes, including neuregulin 1, proline dehydrogenase and dysbindin. Interestingly, these genes point more towards a role for the glutamate pathway rather than the dopamine pathway in schizophrenia. We have attempted to replicate some of these findings in schizophrenic patients from SW China, and we find significant association with a novel neuregulin 1 haplotype, with proline dehydrogenase polymorphisms, but not with catechol-O-methyltransferase (COMT). The replication of neuregulin 1 association on chromosome 8p by several investigators is the most convincing to date, and the presence of a syndrome similar to dementia praecox of 8p linked families, and the lack of linkage of bipolar disorder to this region is a testament to the ideas of Kraepelin more than 100 years ago.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
14Eur. J. Pharmacol. 2003 Nov 480: 177-84
PMID14623361
TitleThe genetics of schizophrenia: glutamate not dopamine?
AbstractThe major targets of current drugs used in mental health, such as neurotransmitter receptors and transporters, are based on serendipitous findings from several decades ago, and there is currently a severe drought of new drug targets. There is a pressing need for novel drugs, and much hope has been placed on the use of molecular genetics to help define them. However, despite evidence for a genetic basis to schizophrenia stretching back for over a century, and a heritability of about 80%, the identification of susceptibility genes has been an uphill struggle. Candidate gene studies, which have generally focussed on obvious candidates from the dopamine and serotonin systems, as well as genes involved in brain development, have not generally been successful, although meta-analysis indicates that the dopamine D3 receptor gene (DRD3) and the serotonin receptor gene type 2A (HTR2A) may have a very small influence on risk. Linkage analysis has provided robust evidence of genetic loci, for example, on chromosomes 8p, 13q and 22q, and also implies shared genetic aetiology with bipolar disorder. The identification of these loci together with advances in genetic technology, especially the characterisation of polymorphisms, the understanding of haplotypes and the development of statistical methods, has lead to the identification of several plausible susceptibility genes, including neuregulin 1, proline dehydrogenase and dysbindin. Interestingly, these genes point more towards a role for the glutamate pathway rather than the dopamine pathway in schizophrenia. We have attempted to replicate some of these findings in schizophrenic patients from SW China, and we find significant association with a novel neuregulin 1 haplotype, with proline dehydrogenase polymorphisms, but not with catechol-O-methyltransferase (COMT). The replication of neuregulin 1 association on chromosome 8p by several investigators is the most convincing to date, and the presence of a syndrome similar to dementia praecox of 8p linked families, and the lack of linkage of bipolar disorder to this region is a testament to the ideas of Kraepelin more than 100 years ago.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
15Pharmacogenomics J. 2003 -1 3: 356-61
PMID14610521
TitleEffect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone.
AbstractRisperidone 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
16Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Apr 126B: 16-8
PMID15048642
Title102T/C SNP in the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia in two southern Han Chinese populations: lack of association.
AbstractSerotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter that occupies a uniquely important place in neurobiology because of its role in many physiologic processes such as sleep, appetite, thermoregulation, pain perception, hormone secretion, and sexual behavior. Serotonin dysfunction has been implicated in the pathogenesis of schizophrenia. Previous studies have shown an association between the T102C polymorphism of the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia. However, many negative findings have also been reported. We analyzed the T102C polymorphism of HTR2A of schizophrenic patients in two southern Chinese populations (n = 291) and matched controls (n = 307). No significant positive association was observed between either of the polymorphisms and all schizophrenics, nor was the polymorphisms and any population of schizophrenia. These data did not provide evidence for a contribution of the 102T/C SNP of HTR2A gene to susceptibility to the southern Han Chinese schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
17Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Apr 126B: 16-8
PMID15048642
Title102T/C SNP in the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia in two southern Han Chinese populations: lack of association.
AbstractSerotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter that occupies a uniquely important place in neurobiology because of its role in many physiologic processes such as sleep, appetite, thermoregulation, pain perception, hormone secretion, and sexual behavior. Serotonin dysfunction has been implicated in the pathogenesis of schizophrenia. Previous studies have shown an association between the T102C polymorphism of the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia. However, many negative findings have also been reported. We analyzed the T102C polymorphism of HTR2A of schizophrenic patients in two southern Chinese populations (n = 291) and matched controls (n = 307). No significant positive association was observed between either of the polymorphisms and all schizophrenics, nor was the polymorphisms and any population of schizophrenia. These data did not provide evidence for a contribution of the 102T/C SNP of HTR2A gene to susceptibility to the southern Han Chinese schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
18Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Apr 126B: 16-8
PMID15048642
Title102T/C SNP in the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia in two southern Han Chinese populations: lack of association.
AbstractSerotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter that occupies a uniquely important place in neurobiology because of its role in many physiologic processes such as sleep, appetite, thermoregulation, pain perception, hormone secretion, and sexual behavior. Serotonin dysfunction has been implicated in the pathogenesis of schizophrenia. Previous studies have shown an association between the T102C polymorphism of the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia. However, many negative findings have also been reported. We analyzed the T102C polymorphism of HTR2A of schizophrenic patients in two southern Chinese populations (n = 291) and matched controls (n = 307). No significant positive association was observed between either of the polymorphisms and all schizophrenics, nor was the polymorphisms and any population of schizophrenia. These data did not provide evidence for a contribution of the 102T/C SNP of HTR2A gene to susceptibility to the southern Han Chinese schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
19Schizophr. Res. 2004 Aug 69: 301-5
PMID15469201
TitleNo association of the T102C polymorphism of the serotonin 2A receptor gene (HTR2A) with suicidality in schizophrenia.
AbstractAdditional evidence for a role of serotonin (5-HT) in the pathogenesis of suicidal behavior is provided by a recent report that the 5-HT2A (HTR2A) T102C polymorphism was associated with suicidality in patients with major depression. Three other studies have, however, failed to find an association between this polymorphism and suicidality in major depression. The goal of the present study was to test the association of allele C of T102C HTR2A polymorphism with suicidality in patients with schizophrenia or schizoaffective disorder. Seventy-one patients with DSM-III-R diagnosis of schizophrenia or schizoaffective disorder were included in the study. Patients were genotyped for the T102C HTR2A polymorphism. Information about lifetime suicidality was obtained during the course of SADS interviews. In addition, current suicidality was assessed by the Hamilton Depression Scale in 46 patients. There were no significant differences in allele frequencies and genotype distributions between suicidal and non-suicidal patients using lifetime or current suicidality measures. The results of this study did not demonstrate a robust association of the allele C of the T102C HTR2A polymorphism with lifetime or current suicidality in patients with schizophrenia. However, the mean Hamilton Depression Scale item for current suicidality was significantly higher in patient with genotype T/C compared to those with genotype C/C (p = 0.01) and marginally higher than for the patients with genotype T/T (p=0.06). The relatively small sample size suggests a study with a larger sample and greater power would be of interest.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
20Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 May 127B: 51-9
PMID15108180
TitleMethylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation.
AbstractFine-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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
21Eur. J. Hum. Genet. 2004 Jul 12: 535-41
PMID15083167
TitleAssociation between schizophrenia and DRD3 or HTR2 receptor gene variants.
Abstractschizophrenia is a severe and common psychiatric disorder afflicting 1% of the world population. A role of many neurotransmitter receptors in schizophrenia was suggested by an association with several polymorphisms located in their coding regions. In this study we examined the contribution of the T-102C and A-206G transitions in the 5-HTR2A and DRD3 receptor genes respectively to genetic susceptibility and phenotypic expression of schizophrenia disorder within the Greek population. We determined by PCR and RFLP analysis the genotype for the above polymorphisms in 114 schizophrenic hospitalized individuals and 192 control samples. In contrast to previous reports from large European multicentre studies, which indicate significant correlation between schizophrenia and C-102 allele of the T-102C polymorphism, in this study we observed a statistically significant overall association between the disorder and allele T-102 (P<0.0001, odds ratio (OR)=2.11, 95% CI=1.48-3.02). We also found a highly significant excess of the T-102/C-102 and C-102/C-102 genotypes in the normal group (P<0.001). Comparison of the patients with the controls for the DRD3 polymorphism (A-206G transition) showed marginally nonsignificant differences in the genotypic (P=0.054) and no significance in the allelic (P=0.163) frequencies. However, the A-206/A-206 genotype seems to positively contribute to the disorder appearance, when compared to A-206/G-206 as genotype base line risk (P=0.016, OR=1.88, 95% CI=1.09-3.26). In conclusion, from genetic association analysis of this schizophrenic population, a significant association is clearly determined between the HTR2 genetic polymorphism and the presence of schizophrenic disorder, manifested as increased risk of schizophrenia for carriers of the T-102 allele.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
22Eur. J. Hum. Genet. 2004 Jul 12: 535-41
PMID15083167
TitleAssociation between schizophrenia and DRD3 or HTR2 receptor gene variants.
Abstractschizophrenia is a severe and common psychiatric disorder afflicting 1% of the world population. A role of many neurotransmitter receptors in schizophrenia was suggested by an association with several polymorphisms located in their coding regions. In this study we examined the contribution of the T-102C and A-206G transitions in the 5-HTR2A and DRD3 receptor genes respectively to genetic susceptibility and phenotypic expression of schizophrenia disorder within the Greek population. We determined by PCR and RFLP analysis the genotype for the above polymorphisms in 114 schizophrenic hospitalized individuals and 192 control samples. In contrast to previous reports from large European multicentre studies, which indicate significant correlation between schizophrenia and C-102 allele of the T-102C polymorphism, in this study we observed a statistically significant overall association between the disorder and allele T-102 (P<0.0001, odds ratio (OR)=2.11, 95% CI=1.48-3.02). We also found a highly significant excess of the T-102/C-102 and C-102/C-102 genotypes in the normal group (P<0.001). Comparison of the patients with the controls for the DRD3 polymorphism (A-206G transition) showed marginally nonsignificant differences in the genotypic (P=0.054) and no significance in the allelic (P=0.163) frequencies. However, the A-206/A-206 genotype seems to positively contribute to the disorder appearance, when compared to A-206/G-206 as genotype base line risk (P=0.016, OR=1.88, 95% CI=1.09-3.26). In conclusion, from genetic association analysis of this schizophrenic population, a significant association is clearly determined between the HTR2 genetic polymorphism and the presence of schizophrenic disorder, manifested as increased risk of schizophrenia for carriers of the T-102 allele.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
23Schizophr. Res. 2004 Mar 67: 53-62
PMID14741324
TitleMeta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia.
AbstractA meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13. The gene HTR2A, which codes for the 5HT2a receptor, is located in this area. The T102C single nucleotide polymorphism of HTR2A has been the subject of much research. The production of the C-allele form of HTR2A is significantly less than that of the T-allele form in normal controls and schizophrenic patients. Although the association of schizophrenia with the C allele of HTR2A was confirmed by a meta-analysis 5 years ago, there was a continuous debate because negative findings were also considerable, which may have been due to ethnic differences in association. We performed another meta-analysis, since the number of available studies of this association has recently doubled. In the meta-analysis of 31 case-control association studies, we found a significant association between the C allele of the T102C polymorphism and schizophrenia, which was more pronounced in European samples than in the entire sample. We found significant heterogeneity in the allele-wise analysis (C vs. T) and homozygous genotype-wise analysis (CC vs. TT), both of which were at least partially explained by differences between samples from Asian and European countries. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, indicating strong genetic differences and noncombinability of data between European and East Asian populations. Interestingly, the frequency of the T allele was much higher in East Asian patients and controls (59.5% and 57.5%, respectively) than in European patients and controls (40% and 43.5%, respectively). In five family-based association studies, we did not find significant evidence for association of the C allele with schizophrenia; yet, the pooled OR was 1.3 (95% CI=0.9-1.8, z=1.47, p=0.14), which is consistent with the results of the case-control studies. The effects of other genes, environmental effects on DNA methylation, or different methods of classification may be the causes for such heterogeneity, but more study in this area is needed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
24Schizophr. Res. 2004 Mar 67: 53-62
PMID14741324
TitleMeta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia.
AbstractA meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13. The gene HTR2A, which codes for the 5HT2a receptor, is located in this area. The T102C single nucleotide polymorphism of HTR2A has been the subject of much research. The production of the C-allele form of HTR2A is significantly less than that of the T-allele form in normal controls and schizophrenic patients. Although the association of schizophrenia with the C allele of HTR2A was confirmed by a meta-analysis 5 years ago, there was a continuous debate because negative findings were also considerable, which may have been due to ethnic differences in association. We performed another meta-analysis, since the number of available studies of this association has recently doubled. In the meta-analysis of 31 case-control association studies, we found a significant association between the C allele of the T102C polymorphism and schizophrenia, which was more pronounced in European samples than in the entire sample. We found significant heterogeneity in the allele-wise analysis (C vs. T) and homozygous genotype-wise analysis (CC vs. TT), both of which were at least partially explained by differences between samples from Asian and European countries. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, indicating strong genetic differences and noncombinability of data between European and East Asian populations. Interestingly, the frequency of the T allele was much higher in East Asian patients and controls (59.5% and 57.5%, respectively) than in European patients and controls (40% and 43.5%, respectively). In five family-based association studies, we did not find significant evidence for association of the C allele with schizophrenia; yet, the pooled OR was 1.3 (95% CI=0.9-1.8, z=1.47, p=0.14), which is consistent with the results of the case-control studies. The effects of other genes, environmental effects on DNA methylation, or different methods of classification may be the causes for such heterogeneity, but more study in this area is needed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
25Mol. Psychiatry 2004 Jan 9: 109-14
PMID14699448
TitleThe serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain.
AbstractThe serotonin-2A (HTR2A) receptor is a molecule of particular interest in biological psychiatry, as it is an important target for psychotropic drugs, and altered HTR2A expression has been found in several neuropsychiatric conditions, including depression and schizophrenia. Genetic association has been reported between a synonymous 102T/C polymorphism in the gene encoding HTR2A and a number of clinical phenotypes, including schizophrenia, clozapine response, psychotic symptoms in Alzheimer's disease and certain features of depression. Given that there are no known effects of the 102T/C polymorphism on the structure of the receptor, attention has switched to the possibility that the observations of both altered expression and genetic association point to functional sequence variants that alter expression of the HTR2A gene. Moreover, data have been presented recently suggesting that mRNAs containing the 102T- and C-alleles are differentially expressed. This suggests a direct effect of the variant itself on mRNA levels, or the influence of a distinct regulatory variant, such as the -1438A/G promoter polymorphism, with which it is in perfect linkage disequilibrium. The present study tested this hypothesis by employing a highly accurate quantitative allele- specific primer extension assay to measure the relative expression of brain mRNAs carrying each allele in 23 individuals heterozygous for the 102T/C polymorphism. Comparison between allele ratios derived from genomic DNA and mRNA from several cortical regions revealed that the 102C- and T-alleles are expressed identically. Furthermore, the absence of any interindividual variability in relative mRNA allele ratio suggests that the HTR2A locus is unlikely to contain common polymorphisms or epigenetic modification that alter HTR2A mRNA levels in adult brain, and essentially exclude such phenomena as a potential explanation for the altered expression and genetic associations that have been reported to date.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
26Pharmacogenomics 2005 Mar 6: 139-49
PMID15882132
TitlePharmacogenetic studies of response to risperidone and other newer atypical antipsychotics.
AbstractRisperidone 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
27Am J Pharmacogenomics 2005 -1 5: 149-60
PMID15952869
TitleGenetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope.
AbstractNo 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
28Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 35-41
PMID16281377
Title[A study of some genes related to serotoninergic and dopaminergic systems and auditory evoked-potentials (P300) in patients with schizophrenia and spectrum disorders and their first-degree relatives].
AbstractThe changes of P300 parameters (lower amplitude and increased latency) are thought to be the most prominent phenomena of schizophrenia. A role of gene polymorphism in P300 generation was supported by several associative studies in psychiatrically well subjects and patients with mental disorders. We studied P300 parameters and the following polymorphisms: T102C for the serotonin receptor type 2A (5-HTR2A) gene, the 5-HTTLPR for the serotonin transporter gene, -809G/A, -616G/C N -52C/T SNPs in the promoter region of the dopamine D4 receptor (DRD4) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) in 74 patients with schizophrenia and spectrum disorders and 71 their first-degree relatives. No association was found between serotonergic system genes and P300. The -809G/A DRD4 gene polymorphism was related to amplitude in all frontal leads (p=0,01) in patients. In relatives, an association was observed between -521C/T DRD4 variants and latency (p=0,005) as well as between the COMT gene polymorphism and P300 amplitude (p=0,004) at the central lead. Thus, the genes involved in dopaminergic system play a role in P300 generation both in patients with schizophrenia and spectrum disorders and their relatives.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
29Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50
PMID16270244
Title[Genetic risk factors in schizophrenia].
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
30Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005 Oct 22: 575-6
PMID16215954
Title[No association of -1438G/A polymorphism in promoter region of 5-HT2A receptor gene with antipsychotic agent-induced weight gain].
AbstractTo investigate whether the -1438G/A polymorphism in the promoter region of 5-HTR2A gene associates with the weight gain following antipsychotic agents (APS) acute treatment in schizophrenic patients.
Eighty-four Chinese Han patients with schizophrenia at the first onset were recruited from among 70 nuclear families. The polymorphism of 5-HTR2A gene was determined with PCR-RFLP technique. Body weight was measured in the patients on admission after 10 weeks of treatment with risperidone or chlorpromazine.
There were no statistically significant differences in the distribution frequencies of genotype (chi2: 0.172, v1, P > 0.05) and allele (chi2: 0.121, v1, P > 0.05) of -1438G/A polymorphism of 5-HTR2A gene between subgroups (weight gain >or= 7% or < 7%). Likewise, there was no significant difference in weight gain between genotype groups. By means of transmission disequilibrium test and quantitative transmission disequilibrium test, no significant association between the -1438G/A polymorphism of 5-HTR2A gene and weight gain was observed.
5-HTR2A gene -1438G/A polymorphism was probably not associated with APS-induced weight gain in Chinese Han patients with schizophrenia in this study.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
31Ann. Med. 2005 -1 37: 121-9
PMID16026119
TitleHTR2A: association and expression studies in neuropsychiatric genetics.
AbstractOver the last decade the gene encoding 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A) has been implicated as a functional candidate in many neuropsychiatric phenotypes including: schizophrenia, attention deficit hyperactivity disorder (ADHD), affective disorders, eating disorders, anxiety disorders, obsessive-compulsive disorder, suicide and Alzheimer's disease (AD). Different studies have tested for genetic association (case-control and family-based studies), protein expression (receptor binding assays), transcriptional expression (mRNA assays) and allelic expression. In this review we examine and summarize these findings in various neuropsychiatric phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
32Curr Psychiatry Rep 2005 Apr 7: 143-51
PMID15802092
TitleMeta-analysis in psychiatric genetics.
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
33Neurosci. Res. 2005 Jun 52: 195-9
PMID15893580
TitleNo evidence for interaction between 5-HT2A receptor and serotonin transporter genes in schizophrenia.
AbstractThis study was to aim at investigating the potential interaction for the serotonin receptor gene (5-HTR) 2A and serotonin transporter gene (5-HTTLPR) polymorphisms in the development of schizophrenia, as well as the interaction of the two polymorphisms in relation with symptomatology, family history, age of onset and antipsychotic response. Genomic DNA analysis with polymerase chain reaction (PCR) was used for the genotyping. One hundred and eleven (111) patients with schizophrenia and 172 normal controls participated in the study. We did not find any association between the individual polymorphism and schizophrenia. The significant interaction effect between 5-HTTLPR and 5-HTR2A polymorphisms on the development of schizophrenia as well as on the antipsychotics response, family history, symptomatology and age at onset, was not found. However, subject with 5-HTR2A*TT genotype were found to have lower age of onset, compared to their counterparts (p=0.01). These results suggest that the interaction between 5-HTTLPR and 5-HTR2A polymorphisms may not contribute to susceptibility to schizophrenia as well as some clinical factors such as antipsychotic response, at least in the Korean population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
34Neurosci. Res. 2005 Aug 52: 342-6
PMID15882913
TitleThe KPNA3 gene may be a susceptibility candidate for schizophrenia.
AbstractThe present study investigated the possible association of the KPNA3 locus in the 13q14 region with schizophrenia. We detected 7 single nucleotide polymorphisms (SNPs) on 13q14, one (rs6313) present at the HTR2A locus and the other 6 at the KPNA3 locus, among 124 British family trios consisting of mother, father and affected offspring with schizophrenia. The transmission disequilibrium test (TDT) showed allelic association for rs3736830 (chi(2)=8.66, P=0.003), rs2181185 (chi(2)=3.86, P=0.049) and rs626716 (chi(2)=5.82, P=0.016), but not for rs6313 (chi(2)=0.009, P=0.926). The global P-value was 0.029 for 1000 permutations with the TDT. The 2-SNP haplotype analysis showed a disease association for the rs2273816-rs3736830 haplotypes (chi(2)=7.63, d.f.=2, P=0.022), the rs3736830-rs2181185 haplotypes (chi(2)=10.30, d.f.=2, P=0.006) and the rs2181185-rs3782929 haplotypes (chi(2)=9.26, d.f.=2, P=0.01). The global P-value was 0.034 for 1000 permutations with the 2-SNP haplotype analysis. The 6-SNP haplotype system also showed a weak association with the illness (chi(2)=15.62, d.f.=8, P=0.048), although the 1-d.f. test did not show the association for nine individual haplotypes when a P-value was corrected by the Bonferroni corrections. The present study suggests that the KPNA3 may contribute genetically to schizophrenia in a small effect size.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
35Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005 Oct 22: 575-6
PMID16215954
Title[No association of -1438G/A polymorphism in promoter region of 5-HT2A receptor gene with antipsychotic agent-induced weight gain].
AbstractTo investigate whether the -1438G/A polymorphism in the promoter region of 5-HTR2A gene associates with the weight gain following antipsychotic agents (APS) acute treatment in schizophrenic patients.
Eighty-four Chinese Han patients with schizophrenia at the first onset were recruited from among 70 nuclear families. The polymorphism of 5-HTR2A gene was determined with PCR-RFLP technique. Body weight was measured in the patients on admission after 10 weeks of treatment with risperidone or chlorpromazine.
There were no statistically significant differences in the distribution frequencies of genotype (chi2: 0.172, v1, P > 0.05) and allele (chi2: 0.121, v1, P > 0.05) of -1438G/A polymorphism of 5-HTR2A gene between subgroups (weight gain >or= 7% or < 7%). Likewise, there was no significant difference in weight gain between genotype groups. By means of transmission disequilibrium test and quantitative transmission disequilibrium test, no significant association between the -1438G/A polymorphism of 5-HTR2A gene and weight gain was observed.
5-HTR2A gene -1438G/A polymorphism was probably not associated with APS-induced weight gain in Chinese Han patients with schizophrenia in this study.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
36Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50
PMID16270244
Title[Genetic risk factors in schizophrenia].
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
37Fortschr Neurol Psychiatr 2005 Nov 73 Suppl 1: S44-50
PMID16270244
Title[Genetic risk factors in schizophrenia].
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
38Biol. Psychiatry 2006 Dec 60: 1331-5
PMID17069769
TitleMonoallelic and unequal allelic expression of the HTR2A gene in human brain and peripheral lymphocytes.
AbstractThe 102T/C polymorphism of the serotonin 2A receptor (HTR2A) gene is reported to be associated with schizophrenia and other diseases and phenotypes. Altered HTR2A expression has been found in relation to several neuropsychiatric conditions, including depression and schizophrenia. Studies of expression of HTR2A messenger RNA (mRNA) and protein in postmortem brains suggest that the 102C allele might be less transcriptionally active than the T allele. However, equal expression of both alleles has also been reported.
We performed primer extension assays to measure relative expression of allele-specific HTR2A transcripts in mRNAs isolated from the prefrontal cortex of 31 individuals with schizophrenia and from peripheral lymphocytes (PBLs) of 31 healthy individuals heterozygous for 102T/C. We also examined the allele transmission pattern of HTR2A in PBLs of nine families.
Analyses of DNA and mRNA revealed that 102C is expressed but at lower levels than 102T in brains. In contrast to the biallelic expression observed in brains, monoallelic expression of HTR2A was common in PBLs. However, a family study revealed that imprinting was not responsible for the monoallelic expression in PBLs.
The present study revealed a tissue-specific modification of HTR2A expression, which makes allelic and epiallelic analyses necessary for genetic epidemiologic and pharmacogenomic studies of HTR2A.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
39Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19
PMID17239033
TitleMolecular genetics of bipolar disorder and depression.
AbstractIn this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
40Vestn. Akad. Med. Nauk SSSR 2007 -1 -1: 3-8
PMID17500207
Title[The molecular-genetic aspects of differentiation of schizoaffective psychosis and attack-like progressive schizophrenia].
AbstractTo clarify nosologic differences between schizoaffective psychosis (SAP) and attack-like progressive schizophrenia at molecular-genetic level, the genetic polymorphism of serotonin receptor type 2A (5HTR2A), serotonin transporter (5-HTTLRP), and brain-derived neurotrophic factor (BDNF) was studied in 563 patients with schizophrenia (mean age 37.7+/-14.4 years, age at disease onset 26.7+/-11.4 years), and 171 patients with SAP (mean age 30.7+/-11.6 years, age at disease onset 24.9+/-8.5 years). The control group consisted of 536 psychiatrically well subjects. Clinical symptoms and personal features were evaluated as well. By comparison with schizophrenic patients, those with SAP were featured by subtle negative symptoms and personality changes that supported the evidence that SAP is a disorder with a favorable outcome. Molecular-genetic studies revealed higher frequencies of S allele and SS genotype (5-HTTLPR polymorphism), which are thought to be associated with depression and depressive symptoms, and higher frequency of BDNF genotypes, containing Met allele, in combination with 5-HTTLRP genotypes containing L allele, in patients with SAP as compared to the schizophrenic group. C allele and CC genotype (T102C 5-HTR2A polymorphism) frequencies were higher in both groups of patients vs. controls. In conclusion, the results confirm the concept considering SAP an independent nosologic category.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
41Psychiatry Res 2007 Jun 151: 243-8
PMID17407792
TitleParent-of-origin effect and genomic imprinting of the HTR2A receptor gene T102C polymorphism in psychosis.
AbstractEvidence that HTR2A receptor gene may be subject to genomic imprinting prompted us to examine a collection of family trios for evidence of an association between the HTR2A T102C polymorphism and psychosis in schizophrenia or bipolar disorder. We also tested for the possibility of imprinting by employing quantitative RT-PCR to measure the relative expression of post-mortem brain mRNA for each allele in 45 subjects who were heterozygous for the T102C polymorphism. We found that the ratio of C102 to 102T allele mRNA expression was the same in major psychoses and healthy controls. There was no genetic association between HTR2A T102C with either schizophrenia or bipolar disorder under the assumption of a parent-of-origin effect, and these data together essentially exclude imprinting at this locus as a potential explanation for the complex inheritance observed in major psychoses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
42DNA Cell Biol. 2007 Aug 26: 527-31
PMID17688403
TitleAssociation of serotonin 2A receptor and lack of association of CYP1A2 gene polymorphism with tardive dyskinesia in a Turkish population.
AbstractThe aim of this study was to investigate the possible association of serotonin 2A receptor gene (HTR2A) -1438 G/A polymorphism and CYP1A2 gene 163C/A polymorphism with tardive dyskinesia (TD) in a Turkish population. A total of 47 patients with persistent TD, 80 patients who were consistently without TD, and 100 healthy controls were included in this study. The polymorphic regions of -1438 G/A polymorphism of HTR2A receptor gene (rs6311) and 163C/A of CYP1A2 (rs762551) gene were amplified using polymerase chain reaction (PCR), followed by digestion with restriction enzymes MspI and Bsp1201. Genotype and allele frequencies were calculated by the chi(2)-test. Crude and adjusted odds ratios (ORs) were estimated, and 95% confidence intervals (CIs) were computed by multivariate logistic regression analysis. The genotype and allele frequencies of HTR2A and CYP1A2 gene were similar in schizophrenia with TD, schizophrenia without TD, and healthy controls. The logistic regression analysis showed that cumulative exposure to antipsychotic drugs for every year (p = 0.003; OR = 1.15; CI = 1.07-1.23), and AA genotype of HTR2A gene (p = 0.0258; OR = 4.34; CI = 1.19-15.81) are risk factors for TD. The same logistic regression model showed no association between CYP1A2 polymorphism and TD. The results of the present study seem to indicate that HTR2A gene polymorphism influences the tendency to express TD following prolonged antipsychotic drug exposure in Turkish schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
43Eur. Psychiatry 2007 Apr 22: 167-70
PMID17240119
TitleSupportive evidence for the association between the T102C 5-HTR2A gene polymorphism and schizophrenia: a large-scale case-control and family-based study.
AbstractSerotonin type 2A receptors (5-HTR2A) have long been implicated in schizophrenia pathology. A decreased number of these receptors were found in postmortem brain studies of schizophrenic patients as well as in experiments using neuroimaging techniques. Molecular genetic studies revealed that the T102C polymorphism of the 5-HTR2A gene is associated with schizophrenia, with the CC genotype frequency being higher in patients compared to healthy controls. However the association was not confirmed in all studies. We carried out a replication study, which aimed at searching for association between this polymorphism and schizophrenia in a large samples of patients (n=919), their psychiatrically well first-degree relatives (n=330) and screened controls (n=500). The C allele and the CT+CC genotype frequencies were significantly higher in patients than in controls (chi2=5.1; df=1; p=0.02; OR 1.2, 95% CI 1.0-1.4) and chi2=5.4; df=1; p=0.02; OR 1.4, 95% CI 1.1-1.8 respectively). In a family-based study, the transmission disequilibrium test (TDT) and the family-based association test (FBAT) did not show a preferential transmission of any allele. In conclusion, our replication study provides further evidence for association between the 5-HTR2A receptor T102C polymorphism and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
44Schizophr. Res. 2007 Feb 90: 123-9
PMID17125970
TitleExtensive linkage disequilibrium mapping at HTR2A and DRD3 for schizophrenia susceptibility genes in the Galician population.
AbstractThe serotonin and dopamine neurotransmitter systems are candidate pathways in the development of schizophrenia because of the assumed causal relationship with the observed symptoms as well as effective targeting of the corresponding receptors by antipsychotic drugs. However, genetic association studies have systematically focused on a limited set of genes and single nucleotide polymorphisms (SNPs), including T102C at HTR2A and Ser9Gly at DRD3. Meta-analyses of the associations between these two markers and schizophrenia revealed a true increase in risk, the magnitude of the effect being very low. In the present study we analyzed 260 schizophrenic patients and 354 control subjects from a homogeneous population, the Galician population, using an extensive linkage disequilibrium (LD) mapping approach, genotyping a total of 47 SNPs to test for the existence of additional variants that confer higher risk. We detected nominal significant association with schizophrenia for several haplotype tag SNPs (htSNPs) at HTR2A, although the significance was lost after multiple test corrections. In addition, haplotype analyses involving a sliding window approach, with window size 2 to 4 SNPs, revealed significant differences in frequencies of the DRD3 haplotypes at the 3' half of the gene region. This difference, which remains clearly significant after multiple test corrections (p=0.002, 0.0001, and 0.0025, for window sizes 2, 3, and 4, respectively), was mainly due to over-representation of several rare haplotypes in patients, at the expense of a single common haplotype; this represents interesting evidence of rare haplotypes for susceptibility detected using common htSNPs due to their strong effect.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
45Eur. Psychiatry 2007 Apr 22: 167-70
PMID17240119
TitleSupportive evidence for the association between the T102C 5-HTR2A gene polymorphism and schizophrenia: a large-scale case-control and family-based study.
AbstractSerotonin type 2A receptors (5-HTR2A) have long been implicated in schizophrenia pathology. A decreased number of these receptors were found in postmortem brain studies of schizophrenic patients as well as in experiments using neuroimaging techniques. Molecular genetic studies revealed that the T102C polymorphism of the 5-HTR2A gene is associated with schizophrenia, with the CC genotype frequency being higher in patients compared to healthy controls. However the association was not confirmed in all studies. We carried out a replication study, which aimed at searching for association between this polymorphism and schizophrenia in a large samples of patients (n=919), their psychiatrically well first-degree relatives (n=330) and screened controls (n=500). The C allele and the CT+CC genotype frequencies were significantly higher in patients than in controls (chi2=5.1; df=1; p=0.02; OR 1.2, 95% CI 1.0-1.4) and chi2=5.4; df=1; p=0.02; OR 1.4, 95% CI 1.1-1.8 respectively). In a family-based study, the transmission disequilibrium test (TDT) and the family-based association test (FBAT) did not show a preferential transmission of any allele. In conclusion, our replication study provides further evidence for association between the 5-HTR2A receptor T102C polymorphism and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
46Curr. Med. Chem. 2007 -1 14: 2053-69
PMID17691947
TitleHTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies.
AbstractVariants at the gene encoding for the 5-hydrosytryptamine (serotonin) receptor 2A (HTR2A) have been associated with many psychiatric disorders such as schizophrenia, mood disorders, attention deficit hyperactivity disorder, suicide, anxiety disorders, obsessive-compulsive disorder, eating disorders, and Alzheimer's disease. The studied SNPs differ across studies, in the present review we focused on available evidence with the aim of identifying the overall phenotypic profile of HTR2A variant carriers. We then extensively analyzed all SNPs of the HTR2A gene with criteria of frequency, haplotype blocks, previous evidence, functionality in order to obtain a list of suitable SNPs for future studies that properly cover all possible genetic control of the HTR2A gene. Genetic association studies report conflicting and generally negative results. Most replicated data suggest C allele of the 102 T/C and Tyr452 variants as risk factor for psychosis and antipsychotic response, but the number of not replicating studies does not allow to draw any definite conclusion. Moreover their impact as risk factors is very small. In the other investigated psychiatric fields, evidence shows no involvement or at least a small and not replicated role for HTR2A gene variants. Conflicting and negative results could be due to a real marginal role of this receptor gene variants, or it could be caused by a lack of gene coverage of investigated SNPs. We suggest a wider investigation of the HTR2A gene to better understand its role in psychiatric disorders, preferably complemented with the use of proteomic or metabolomic approaches.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
47Clin. Chem. Lab. Med. 2007 -1 45: 835-8
PMID17617023
TitleAssociation between T102C and A-1438G polymorphisms in the serotonin receptor 2A (5-HT2A) gene and schizophrenia: relevance for treatment with antipsychotic drugs.
AbstractAn involvement of serotonin receptor 2A (5-HT2A) in the aetiology of schizophrenia has been hypothesised. The 5-HT2A receptor also appears to be an important site of action of atypical antipsychotic drugs. Indeed, association between schizophrenia and the T102C silent polymorphism of the 5-HTR2A gene has been reported. Another polymorphism in the promoter region of 5-HTR2A (A-1438G) in linkage disequilibrium with the T102C polymorphism has also been reported. It has been suggested that the A-1438G polymorphism alters promoter activity and expression of 5-HT2A receptors and might be responsible for the associations with schizophrenia and the efficacy of atypical antipsychotics such as risperidone.
We analysed the 5-HTR2A T102C and A-1438G polymorphisms in clinically stable schizophrenia patients (SPs) and healthy volunteers (HVs). We developed an allele-specific PCR-based restriction fragment length polymorphism (PCR-RFLP) method. In SPs, we also described differences across both diagnosis subtypes (paranoid vs. non-paranoid) and antipsychotic drug treatment (risperidone vs. other classical antipsychotic drugs).
Two groups of 114 SPs and 142 HVs were studied. The frequency of the 5-HTR2A -1438A allele was higher in SPs than in HVs (0.54 vs. 0.44; p<0.05). The frequency of the 102T allele was also higher among SPs than HVs (0.56 vs. 0.46; p<0.05). These two polymorphisms were in linkage disequilibrium. The percentage of carriers of the 1438A/A and 102T/T alleles was 26% and 15% for SPs and HVs, respectively (p<0.05; odds ratio 1.9). No differences in genotype or allele frequencies were found between paranoid and non-paranoid SPs or between SPs on risperidone and those on classical antipsychotic treatment.
The present study demonstrates a higher frequency of 5-HTR2A -1438A and 102T alleles in SPs compared to HVs.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
48Vestn. Akad. Med. Nauk SSSR 2007 -1 -1: 3-8
PMID17500207
Title[The molecular-genetic aspects of differentiation of schizoaffective psychosis and attack-like progressive schizophrenia].
AbstractTo clarify nosologic differences between schizoaffective psychosis (SAP) and attack-like progressive schizophrenia at molecular-genetic level, the genetic polymorphism of serotonin receptor type 2A (5HTR2A), serotonin transporter (5-HTTLRP), and brain-derived neurotrophic factor (BDNF) was studied in 563 patients with schizophrenia (mean age 37.7+/-14.4 years, age at disease onset 26.7+/-11.4 years), and 171 patients with SAP (mean age 30.7+/-11.6 years, age at disease onset 24.9+/-8.5 years). The control group consisted of 536 psychiatrically well subjects. Clinical symptoms and personal features were evaluated as well. By comparison with schizophrenic patients, those with SAP were featured by subtle negative symptoms and personality changes that supported the evidence that SAP is a disorder with a favorable outcome. Molecular-genetic studies revealed higher frequencies of S allele and SS genotype (5-HTTLPR polymorphism), which are thought to be associated with depression and depressive symptoms, and higher frequency of BDNF genotypes, containing Met allele, in combination with 5-HTTLRP genotypes containing L allele, in patients with SAP as compared to the schizophrenic group. C allele and CC genotype (T102C 5-HTR2A polymorphism) frequencies were higher in both groups of patients vs. controls. In conclusion, the results confirm the concept considering SAP an independent nosologic category.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
49Psychopharmacology (Berl.) 2007 Mar 190: 479-84
PMID17102980
TitleSerotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients.
AbstractPerphenazine, 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
50Schizophr. Res. 2007 Feb 90: 123-9
PMID17125970
TitleExtensive linkage disequilibrium mapping at HTR2A and DRD3 for schizophrenia susceptibility genes in the Galician population.
AbstractThe serotonin and dopamine neurotransmitter systems are candidate pathways in the development of schizophrenia because of the assumed causal relationship with the observed symptoms as well as effective targeting of the corresponding receptors by antipsychotic drugs. However, genetic association studies have systematically focused on a limited set of genes and single nucleotide polymorphisms (SNPs), including T102C at HTR2A and Ser9Gly at DRD3. Meta-analyses of the associations between these two markers and schizophrenia revealed a true increase in risk, the magnitude of the effect being very low. In the present study we analyzed 260 schizophrenic patients and 354 control subjects from a homogeneous population, the Galician population, using an extensive linkage disequilibrium (LD) mapping approach, genotyping a total of 47 SNPs to test for the existence of additional variants that confer higher risk. We detected nominal significant association with schizophrenia for several haplotype tag SNPs (htSNPs) at HTR2A, although the significance was lost after multiple test corrections. In addition, haplotype analyses involving a sliding window approach, with window size 2 to 4 SNPs, revealed significant differences in frequencies of the DRD3 haplotypes at the 3' half of the gene region. This difference, which remains clearly significant after multiple test corrections (p=0.002, 0.0001, and 0.0025, for window sizes 2, 3, and 4, respectively), was mainly due to over-representation of several rare haplotypes in patients, at the expense of a single common haplotype; this represents interesting evidence of rare haplotypes for susceptibility detected using common htSNPs due to their strong effect.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
51Pharmacogenomics 2008 Oct 9: 1437-43
PMID18855532
TitleVariants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia.
AbstractAbnormalities 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
52J Clin Psychiatry 2008 Sep 69: 1416-22
PMID19193342
TitleMultiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study.
AbstractOne of the clinically significant adverse effects of olanzapine treatment is weight gain, which shows substantial inter-individual differences and may be influenced by genetic variation. The aim of this investigation was identification of genetic risk factors associated with olanzapine-induced weight gain.
Inpatients with DSM-IV-TR schizophrenia (N = 164) were administered olanzapine for 8 to 24 (mean +/- SD = 17.9 +/- 9.4) weeks. The clinical background, body mass index (BMI), and clinical response to olanzapine were investigated. Twenty-one loci of diverse candidate genes encoding dopamine, serotonin (5-HT), histamine, and adrenergic receptors, tumor necrosis factor-alpha, ghrelin, adiponectin, and peroxisome proliferator-activated receptor gamma-2, were analyzed. The study was conducted from June 2001 to June 2003 at 4 psychiatric hospitals in Japan.
BMI increased by a mean +/- SD 4.3 +/- 10.7% after treatment with olanzapine (mean +/- SD dose = 15.5 +/- 5.8 mg/day). Olanzapine-induced weight gain correlated negatively with baseline BMI and positively with clinical global improvement and the length of olanzapine treatment (p < .0001), but it did not correlate with the daily dose of olanzapine, concomitant antipsychotics, sex, age, or smoking. Four genetic variants, the 102T allele of HTR2A, the 825T allele of GNB3, the 23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3, were significantly associated with olanzapine-induced weight gain. Stepwise regression analysis revealed that the baseline BMI predicted 12.5% of the weight gain, and the 2 latter genetic factors added 6.8%. The patients with double and triple genetic risk factors showed 5.1% and 8.8% BMI increases, respectively, during olanzapine treatment, whereas the patients with a single or no risk factor showed approximately a 1% BMI increase.
We identified genetic variants of 5-HT(2A) and 5-HT(2C) receptors, the G-protein beta-3 subunit, and the adrenergic receptor beta-3, as genetic risk factors for olanzapine-induced weight gain, and they showed additive genetic effects on weight gain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
53Am J Psychiatry 2008 Apr 165: 497-506
PMID18198266
TitleNo significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics.
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
54Hum Psychopharmacol 2008 Jan 23: 61-7
PMID17924589
TitleCould HTR2A T102C and DRD3 Ser9Gly predict clinical improvement in patients with acutely exacerbated schizophrenia? Results from treatment responses to risperidone in a naturalistic setting.
AbstractThis study seeks to replicate previous results indicating that T102C in the serotonin 2A receptor (HTR2A) and Ser9Gly in the dopamine D3 receptor (DRD3) were associated with a risperidone response to acutely exacerbated schizophrenia, and to determine whether possession of these alleles predicts clinical improvement in a naturalistic setting.
We consecutively recruited 100 schizophrenia patients and assessed clinical improvement after 4 weeks of risperidone treatment.
The patients with T/T in the HTR2A gene showed less clinical improvement than did those with T/C or C/C (p = 0.044). In the case of the DRD3 gene, we did not find statically significant association with clinical improvement (p = 0.061). When patients were categorized into responders and nonresponders, the C allele was more frequent in responders (OR = 2.28, 95%CI = 1.06-4.91, p = 0.039). When combinations of the two polymorphisms were considered, patients who had T/T in the HTR2A gene and encoded Ser/Ser or Ser/Gly from DRD3 gene had a higher propensity to non-responsiveness compared to other subjects (OR = 3.57, 95%CI = 1.10-11.62, p = 0.039).
Our findings suggest that the HTR2A T102C could be a potential indicator of clinical improvement after risperidone treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
55Zh Nevrol Psikhiatr Im S S Korsakova 2008 -1 108: 62-9
PMID18454098
Title[Investigation of association of the brain-derived neurotrophic factor (BDNF) and a serotonin receptor 2A (5-HTR2A) genes with voluntary and involuntary attention in schizophrenia].
AbstractTo investigate the effect of Val66Met BDNF and 5-HTR2A T102C polymorphisms on the characteristics of voluntary and involuntary visual attention, 89 patients with schizophrenia, 91 their well relatives and 163 controls have been studied. Attention was assessed using a modified version of the Munsterberg test. The significant interaction effect of the BDNF, 5-HTR2A and diagnosis on attention characteristics was found (p=0,04). Carriers of the Val/Val genotype demonstrated higher scores of both voluntary and involuntary attention and those with the A1 (T) allele needed more time for the performance of the test. The combination of the A1 allele with a Met BDNF allele was associated with lower scores of voluntary attention and higher scores of involuntary attention. The study confirmed the impairment of selective attention in patients with schizophrenia and their relatives while any pathological changes in involuntary attention were not observed. The effect of genotypes was presented irrespective of diagnostic group studied. The data obtained suggest that carriers of the Val/Val genotype are able to allocate more attentional resources to process external stimuli. At the same time, the possibility that this polymorphism is likely associated with specific visual-spatial abilities than with attention as such or general cognitive resources can not be excluded.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
56Neuropsychopharmacol Hung 2008 Mar 10: 9-14
PMID18771015
TitleTranscriptome alterations in the prefrontal cortex of subjects with schizophrenia who committed suicide.
AbstractTo better understand the pathophysiological events associate with suicide in subjects with schizophrenia, we performed a DNA microarray expression profiling of the frontal cortex of subjects with schizophrenia who committed suicide, subjects with schizophrenia who died of non-suicidal causes and matched control subjects. Simultaneous expression profiling for >40,000 genes was performed using HU133A and HU133B Affymetrix oligonucleotide arrays. We conclude that suicide in schizophrenia is associated with a number of gene expression changes in the prefrontal cortex that are distinct from both of that observed in controls and subjects with schizophrenia who did not commit suicide. Furthermore, the observed gene expression signature contains a prefrontal cortical downregulation of the HTR2A serotonin receptor transcript, strengthening previously reported genetic susceptibility reports. As the observed transcript changes are likely developing over days or weeks, these data argue that the molecular predisposition to suicide develops significantly earlier than the act of suicide occurs. Finally, the presented data also strengthens previous reports of neuroimmune transcriptome disturbances in subjects with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
57Neurosci. Lett. 2008 Apr 435: 95-8
PMID18359159
TitleRelationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population.
AbstractThe proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
58Neurosci. Lett. 2008 Apr 435: 95-8
PMID18359159
TitleRelationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population.
AbstractThe proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
59Psychopharmacology (Berl.) 2008 Jan 195: 579-90
PMID17899021
Title5-HT2A receptor density is decreased in the at-risk mental state.
AbstractCurrent perspectives on the pathophysiology of schizophrenia direct attention to serotonergic (serotonin, 5-HT) dysregulation in the prodrome or at-risk mental state (ARMS).
To study the cerebral 5-HT(2A) receptor (5-HT(2A)R) in the ARMS with [(18)F]altanserin positron emission tomography (PET) and a bolus-infusion paradigm.
We quantified the spatial distribution of 5-HT(2A)R binding potential (BP(1)') in never-medicated subjects assigned to early (n = 6) and late (n = 8) prodromal states of schizophrenia relative to healthy controls (n = 21). Five single nucleotide polymorphisms (SNPs) in the 5-HT(2A)R-encoding gene (HTR2A; 13q14-21) were genotyped to control for a potential bias in BP(1)' due to between-group differences in genotype distributions.
Group comparisons of partial-volume corrected PET data by statistical parametric mapping and confirmatory volume of interest analysis yielded a dissemination of BP(1)' decreases consistent with increasing levels of risk. An additional decrease in caudate BP(1)' was present in subjects who subsequently converted to first-episode psychosis (n = 5), but absent in non-converters (n = 9). Between-group differences were not confounded by a differential distribution of SNP genotypes.
These results suggest a progressive reduction of cortical 5-HT(2A)R density as a surrogate biological measure of increased risk for schizophrenia, irrespective of conversion. Progressive reductions of subcortical 5-HT(2A)R density could provide an indicator of illness activity and help to predict imminent conversion to schizophrenia. Moreover, our findings substantiate the rationale for establishing a phase-specific psychopharmacological intervention in the ARMS that addresses the serotonergic component of vulnerability to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
60J Psychiatr Res 2008 Sep 42: 884-93
PMID18086475
TitleGene polymorphism influencing treatment response in psychotic patients in a naturalistic setting.
AbstractMany 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 Jnkping, 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
61Schizophr Bull 2009 Nov 35: 1163-82
PMID18552348
TitleSchizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.
AbstractMany genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
62J Neural Transm (Vienna) 2009 May 116: 607-13
PMID19352591
TitleGenetic variation of serotonin receptor function affects prepulse inhibition of the startle.
AbstractPrepulse inhibition (PPI) is the attenuation of the startle response towards an instantaneous and intense stimulus when preceded by a weaker non-startling stimulus. Deficits in this sensorimotor gating process have been associated with the pathophysiology of schizophrenia and other psychiatric disorders. Among the neurotransmitters involved in PPI modulation, serotonin (5-HT) has so far received comparably little attention. While a recent pharmacological study suggests an important role of different 5-HT receptor (5-HTR) subtypes in PPI modulation, the mechanisms by which 5-HTR impact on PPI remain to be further elucidated. Therefore, we employed a molecular genetic approach in order to examine whether PPI is associated with two functional 5-HTR gene polymorphisms, 5-HTR1A C-1019G and 5-HTR2A T102C. In a sample of 81 healthy volunteers, we found no significant main effects of the polymorphisms, but a significant interaction effect on PPI at short (50 ms) and mid-long (150 ms) pulse-prepulse intervals. The presence of the 5-HTR2A T allele (reported to result in higher 5-HTR2A expression) led to attenuated PPI only in the absence of the 5-HTR1A G allele (reported to result in reduced 5-HTR1A autoreceptor expression). Our results may indicate that a higher 5-HTR2A expression together with a reduced 5-HTR1A autoreceptor expression and consequently, elevated firing rates of serotonergic neurons results in elevated 5-HTR2A activation by serotonin which could potently attenuate PPI. While further research into the molecular mechanisms underlying this interaction is needed, our results underscore the role of 5-HTR in PPI modulation and further implicate the 5-HTR1A G-1019C and the 5-HTR2A T102C polymorphisms in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
63Neuro Endocrinol. Lett. 2009 -1 30: 343-51
PMID19855357
TitleSerotonin receptor 2A gene polymorphisms and schizophrenia: association with family history, diagnostic subtype and height in patients.
AbstractThe 102T/C single nucleotide polymorphism (SNP) in the 5-hydroxytryptamine receptor 2A (HTR2A) gene has been reported to be associated with schizophrenia. However, SNPs of the HTR2A gene other than the 102T/C have attracted only limited studies in relation to schizophrenia, and also on the whole SNPs of the HTR2A gene have been little studied in relation to clinical parameters in patients. Therefore, the aim of this study was to evaluate the impact of main functionally characterized SNPs of the HTR2A gene on both the schizophrenia and clinical parameters.
Ninety-four patients with schizophrenia and 57 control subjects were genotyped for the -1438A/G, -783A/G, 102T/C and His452Tyr SNPs of the HTR2A gene. The four SNPs were then investigated in relation to the schizophrenia and clinical parameters.
No differences were found in genotype-, allele- or haplotype frequencies between schizophrenia patients and control subjects. However, the 452Tyr variant of the His452Tyr polymorphism occurred more often in patients with a family history of schizophrenia compared with patients without heredity (p=0.028). The 452Tyr variant was also more common in female patients with paranoid schizophrenia than in those with non-paranoid schizophrenia (p=0.018). Moreover, the male patients carrying the A/A or T/T genotypes of the -1438A/G and 102T/C polymorphisms were shorter than those carrying the G/A or C/T genotypes (p=0.007; p=0.006).
The present findings bring further support to the view that the -1438A/G, 102T/C and His452Tyr polymorphisms of the HTR2A gene are connected with a constitutive cellular change that causes susceptibility to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
64Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 70-5
PMID19672240
Title[Serotonin receptor (5-HTR2A) and dysbindin (DTNBP1) genes and component process variables of short-term verbal memory in schizophrenia].
AbstractAn association study of variations in the DTNBP1 (P1763 and P1578) and 5-HTR2A (T102C and A-1438G) genes with short-term verbal memory efficiency and its component process variables was carried out in 405 patients with schizophrenia and 290 healthy controls. All subjects were asked to recall immediately two sets of 10 words. Total recall, List 1 recall, immediate recall or attention span, proactive interference and a number of intrusions were measured. Patients significantly differed from controls by all memory variables. The efficiency of test performance, efficiency of immediate memory, effect of proactive interference as well as number of intrusions were decreased in the group of patients. Both 5-HTR2A polymorphisms were associated with short-term verbal memory efficiency in the combined sample, with the worst performance observed in carriers of homozygous CC (T102C) and GG (A-1438G) genotypes. The significant effect of the P1763 (DTNBP1) marker on the component process variables (proactive interference and intrusions) was found while its effect on the total recall was non-significant. The homozygotes for GG (P1763) had the worst scores. Overall, the data obtained are in line with the conception of DTNBP1 and 5-HTR2A involvement in different component process variables of memory in healthy subjects and patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
65Psychopharmacology (Berl.) 2009 Aug 205: 285-92
PMID19387614
TitleHTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients.
AbstractAripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin 2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining variability in response to aripiprazole.
This study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms (rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia.
After hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects of genetic and clinical factors on PANSS performance after aripiprazole treatment.
We found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment.
The data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients as modified by clinical factors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
66J Clin Psychopharmacol 2009 Feb 29: 65-8
PMID19142110
TitleAssociation between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine.
AbstractSerotonin 2C and 2A receptor (5-HT2C and 5-HT2A) antagonisms are hypothesized to play a role in the metabolic adverse effects induced by olanzapine and clozapine. Associations between polymorphisms in 5-HT2C and 5-HT2A receptor coding genes, HTR2C and HTR2A, with antipsychotic-induced weight gain have been reported. The impact of HTR2C and HTR2A polymorphisms on body mass index (BMI), glucose-insulin homeostasis, and blood lipid levels was evaluated in 46 patients with schizophrenia or schizoaffective disorder and treated with olanzapine (n = 28) or clozapine (n = 18) for at least 6 months. Olanzapine-treated patients with HTR2C haplotype C (-759C, -697C, and 23Ser) had higher BMI (P = 0.029) and C peptide levels (P = 0.029) compared with patients with haplotype B (-759T, -697C, and 23Cys). The frequency of patients homozygous for the HTR2C haplotype A (-759C, -697G, and 23Cys) was significantly higher among clozapine-treated patients with obesity (BMI >/= 30 kg/m) compared with nonobese patients (P = 0.015; odds ratio, 28; 95% confidence interval, 2-380). Patients carrying the HTR2A haplotype 2 (-1438A, 102T, and 452His) had significantly higher C peptide levels compared with haplotype 3 (-1438A, 102T, and 452Tyr) carriers in the olanzapine group (P = 0.034) and in the overall study population (P = 0.019). None of the haplotypes were associated with serum levels of insulin, triglycerides, and cholesterol or with homeostasis model assessment index for insulin resistance. In conclusion, both HTR2C and HTR2A gene polymorphisms seem to be associated with the occurrence of metabolic abnormalities in patients treated with olanzapine or clozapine.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
67Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Apr 150B: 411-7
PMID18712714
TitleGenetic variation in the serotonin 2A receptor and suicidal ideation in a sample of 270 Irish high-density schizophrenia families.
AbstractGenetic variation in the serotonin 2A receptor (HTR2A) has been associated with both schizophrenia and suicidal behavior. Our sample comprised 270 Irish high-density schizophrenia families (n = 1,408 subjects, including 755 with psychotic illness). Diagnoses were generated using a modified SCID. All patients who had at least one episode of psychosis were rated on the Operation Criteria Checklist for Psychotic Illness (OPCRIT). Lifetime history of suicidal ideation was determined from medical records and psychiatric interviews and was scored in the OPCRIT. Twelve SNPs were selected for study. Ten of these were tagSNPs derived from HapMap data, along with His452Tyr and T102C. We tested for association with psychotic illness as a whole, as well as stratified by the presence of suicidal ideation, using FBAT and PDTPHASE. Single-marker as well as haplotype-based tests using a "sliding window" approach were performed. We observed several 2, 3, and 4 marker haplotypes near the 3' end of the gene that were over-transmitted to psychotic subjects (0.02 HTR2A as a susceptibility gene for psychotic illness, or for suicidal ideation within psychotic illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
68Psychopharmacology (Berl.) 2009 Aug 205: 285-92
PMID19387614
TitleHTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients.
AbstractAripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin 2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining variability in response to aripiprazole.
This study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms (rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia.
After hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects of genetic and clinical factors on PANSS performance after aripiprazole treatment.
We found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment.
The data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients as modified by clinical factors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
69Zh Nevrol Psikhiatr Im S S Korsakova 2010 -1 110: 48-52
PMID21183914
Title[Molecular-genetic approach to the clinical and nosologic differentiation of schizoaffective disorder].
AbstractThe aim of the study was to find molecular-genetic variants associated with nosologically independent schizoaffective disorder (SAD) which clinical presentations had been specified earlier. Authors studied a sample of 230 patients including 39 with "nuclear" (nosologically independent) and marginal (intermediate) variants of SAD, 53 with schizophrenia with schizoaffective states and 81 with schizophrenia with affective disorders in the structure of psychotic attacks. In these groups, authors studied the following polymorphisms: 5-HTTLPR, Val66Met BDNF, T102C 5-HTR2A and ?677? MTHFR. Frequencies of genotypes were compared to those in a sample of healthy controls (328 people). It has been shown that the "nuclear" variant has a genetic profile represented by a combination of genetic variants (SS*ValVal*TT*CC) that distinguishes this clinical entity from other groups and controls. The results may be used as an additional criteria for clinical and nosological differentiation of SAD from schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
70Molecules 2010 Jul 15: 4875-89
PMID20657396
TitleMachine learning techniques for single nucleotide polymorphism--disease classification models in schizophrenia.
AbstractSingle nucleotide polymorphisms (SNPs) can be used as inputs in disease computational studies such as pattern searching and classification models. schizophrenia is an example of a complex disease with an important social impact. The multiple causes of this disease create the need of new genetic or proteomic patterns that can diagnose patients using biological information. This work presents a computational study of disease machine learning classification models using only single nucleotide polymorphisms at the HTR2A and DRD3 genes from Galician (Northwest Spain) schizophrenic patients. These classification models establish for the first time, to the best knowledge of the authors, a relationship between the sequence of the nucleic acid molecule and schizophrenia (Quantitative Genotype-Disease Relationships) that can automatically recognize schizophrenia DNA sequences and correctly classify between 78.3-93.8% of schizophrenia subjects when using datasets which include simulated negative subjects and a linear artificial neural network.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
71Genet. Mol. Res. 2010 -1 9: 1274-8
PMID20623453
TitleLinkage of schizophrenia with TPH2 and 5-HTR2A gene polymorphisms in the Malay population.
AbstractThe serotoninergic system has been implicated in the etiology of schizophrenia and other behavioral disorders. Association studies have focused on the tryptophan hydroxylase 2 gene (TPH2) and the 5-hydroxytryptamine receptor 2A gene (5-HTR2A). We genotyped two single-nucleotide polymorphisms, A1438G of 5-HTR2A and intronic rs1386494 of TPH2 in the Malay population, using a sample size of 289 schizophrenic patients and 130 healthy controls. We found a significant association of A1438G of 5-HTR2A with schizophrenia in Malays. On the other hand, TPH2 polymorphism was not associated with schizophrenia. This is the first genetic association study concerning schizophrenia in the Malay population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
72Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 May 34: 639-44
PMID20211215
TitleAssociation analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population.
AbstractAbnormalities in glutaminergic neural transmission have been suggested to be involved in the pathogenesis of schizophrenia. A recent study reported that alterations in the 5-HT2A-mGluR2 complex may be involved in neural transmission in the schizophrenic cortex. In addition, methamphetamine-induced psychosis is thought to be similar to schizophrenia. Therefore, we conducted a case-control study with Japanese samples (738 schizophrenia patients, 196 methamphetamine-induced psychosis patients, and 802 controls) to evaluate the association and interaction between GRM2, HTR2A and schizophrenia.
We selected three 'tagging SNPs' in GRM2, and two biologically functional SNPs in HTR2A (T102C and A1438G), for the association analysis.
We detected a significant association between methamphetamine-induced psychosis and GRM2 in a haplotype-wise analysis, but not HTR2A. We did not detect an association between GRM2 or HTR2A and schizophrenia. In addition, no interactions of GRM2 and HTR2A were found in methamphetamine-induced psychosis or schizophrenia. We did not detect any novel polymorphisms in GRM2 when we performed a mutation search using methamphetamine-induced psychosis samples.
Our results suggested that GRM2 may play a role in the pathophysiology of methamphetamine-induced psychosis but not schizophrenia in the Japanese population. A replication study using larger samples or samples of other populations will be required for conclusive results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
73Molecules 2010 Jul 15: 4875-89
PMID20657396
TitleMachine learning techniques for single nucleotide polymorphism--disease classification models in schizophrenia.
AbstractSingle nucleotide polymorphisms (SNPs) can be used as inputs in disease computational studies such as pattern searching and classification models. schizophrenia is an example of a complex disease with an important social impact. The multiple causes of this disease create the need of new genetic or proteomic patterns that can diagnose patients using biological information. This work presents a computational study of disease machine learning classification models using only single nucleotide polymorphisms at the HTR2A and DRD3 genes from Galician (Northwest Spain) schizophrenic patients. These classification models establish for the first time, to the best knowledge of the authors, a relationship between the sequence of the nucleic acid molecule and schizophrenia (Quantitative Genotype-Disease Relationships) that can automatically recognize schizophrenia DNA sequences and correctly classify between 78.3-93.8% of schizophrenia subjects when using datasets which include simulated negative subjects and a linear artificial neural network.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
74Genet. Mol. Res. 2010 -1 9: 1274-8
PMID20623453
TitleLinkage of schizophrenia with TPH2 and 5-HTR2A gene polymorphisms in the Malay population.
AbstractThe serotoninergic system has been implicated in the etiology of schizophrenia and other behavioral disorders. Association studies have focused on the tryptophan hydroxylase 2 gene (TPH2) and the 5-hydroxytryptamine receptor 2A gene (5-HTR2A). We genotyped two single-nucleotide polymorphisms, A1438G of 5-HTR2A and intronic rs1386494 of TPH2 in the Malay population, using a sample size of 289 schizophrenic patients and 130 healthy controls. We found a significant association of A1438G of 5-HTR2A with schizophrenia in Malays. On the other hand, TPH2 polymorphism was not associated with schizophrenia. This is the first genetic association study concerning schizophrenia in the Malay population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
75Neurosci. Behav. Physiol. 2010 Oct 40: 934-40
PMID20683774
TitlePolymorphism of serotonin receptor genes (5-HTR2A) and Dysbindin (DTNBP1) and individual components of short-term verbal memory processes in Schizophrenia.
AbstractAssociations between polymorphisms in the T102C and A-1438G loci of the 5-HTR2A and the P1763 and P1578 markers of the DTNBP1 gene with the overall productivity and individual subprocesses of shortterm verbal memory were studied in 4-5 patients with schizophrenia and 290 healthy subjects. Subjects were asked to reproduce immediately two lists of 10 words. The overall productivity of reproduction was assessed, along with the reproduction productivity of the first list (immediate memory or general attention), the effect of proactive interference, and the number of intrusions. Patients were significantly different from controls on all measures. Patients showed decreases in overall task performance productivity, in immediate memory productivity, and in the effect of proactive interference; fewer intrusions were seen. Both markers of the 5-HTR2A gene were associated with short-term memory productivity in the combined cohort: assessments were worse in T102C CC and A-1438G GG homozygotes. The P1763 marker of the DTNBP1 gene, conversely, had significant influences on the memory subprocesses reflected in the levels of interference and intrusions but had insignificant influence on overall productivity. Homozygotes for P1763G GG had the worst parameters. Overall, these data are consistent with the concept that these polymorphic genes are involved in different subprocesses of short-term memory both in normal subjects and in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
76Pharmacogenomics J. 2010 Feb 10: 20-9
PMID19636338
TitlePharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome.
AbstractPsychiatric pharmacotherapy with olanzapine is commonplace. We investigated the influence of CYP1A2*1F (-163A, rs762551) and serotonergic polymorphisms on olanzapine serum concentrations and clinical outcome in a naturalistic clinical setting. Included were 124 Caucasian psychiatric inpatients treated with olanzapine for at least 4 weeks with steady-state serum concentrations available for 73 patients. The CYP1A2*1F polymorphism was reported to affect the inducibility of CYP1A2. In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of inducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test. Higher olanzapine concentrations were significantly correlated with better improvement of paranoid and depressive symptoms in patients with schizophrenic disorders (Spearman's r=0.5, P=0.026 and P=0.006, respectively). No relationship between serum concentrations and the side effects (DOTES) score was detected. However, patients with the 5-HTR2A intron 2 (rs7997012) AA genotype suffered from more pronounced side effects compared to carriers of the GA or GG genotype (P=0.018 and P=0.002). Short-term weight gain under olanzapine therapy was significantly lower for 5-HTR2C -759 T-allele carriers (P=0.011). Our data suggest that the CYP1A2*1F/*1F genotype exhibits a significant influence on olanzapine concentrations independent of other inducing factors. Thus, CYP1A2*1F genotyping may be useful for clinical treatment decisions given the fact that olanzapine serum concentrations correlated with treatment response. Side effects and weight gain, however, seem to be more influenced by serotonergic polymorphisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
77Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 May 34: 639-44
PMID20211215
TitleAssociation analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population.
AbstractAbnormalities in glutaminergic neural transmission have been suggested to be involved in the pathogenesis of schizophrenia. A recent study reported that alterations in the 5-HT2A-mGluR2 complex may be involved in neural transmission in the schizophrenic cortex. In addition, methamphetamine-induced psychosis is thought to be similar to schizophrenia. Therefore, we conducted a case-control study with Japanese samples (738 schizophrenia patients, 196 methamphetamine-induced psychosis patients, and 802 controls) to evaluate the association and interaction between GRM2, HTR2A and schizophrenia.
We selected three 'tagging SNPs' in GRM2, and two biologically functional SNPs in HTR2A (T102C and A1438G), for the association analysis.
We detected a significant association between methamphetamine-induced psychosis and GRM2 in a haplotype-wise analysis, but not HTR2A. We did not detect an association between GRM2 or HTR2A and schizophrenia. In addition, no interactions of GRM2 and HTR2A were found in methamphetamine-induced psychosis or schizophrenia. We did not detect any novel polymorphisms in GRM2 when we performed a mutation search using methamphetamine-induced psychosis samples.
Our results suggested that GRM2 may play a role in the pathophysiology of methamphetamine-induced psychosis but not schizophrenia in the Japanese population. A replication study using larger samples or samples of other populations will be required for conclusive results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
78Behav. Genet. 2011 Sep 41: 709-15
PMID21399903
TitleEffect of serotonin-related gene polymorphisms on pathogenesis and treatment response in Korean schizophrenic patients.
AbstractSerotonin has been implicated in the pathophysiology of several psychiatric disorders including schizophrenia. Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. We aimed to investigate the associations of HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T variants with schizophrenia. A total of 202 patients with schizophrenia and 165 normal controls were genotyped for HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T single nucleotide polymorphisms (SNPs). In order to assess the severity of a patient's psychiatric symptoms, the brief psychiatric rating scale (BPRS), the positive and negative symptom scale (PANSS), and the Calgary depression scale for schizophrenia (CDSS) were administered. Genotype and allele frequencies were compared between groups via ?(2) statistics. Associations between the genotypes of candidate SNPs with the severity of symptoms were examined with ANOVA by comparing the mean scores of BPRS, PANSS, and CDSS according to genotype. No significant differences in the genotype distributions and allele frequencies of four SNPs were found between patients with schizophrenia and normal controls. There was a trend towards association of HTR1A C-1019G polymorphism with negative symptom. Negative symptom score of PANSS was lower in the patients with CC genotype than in the G allele carriers. These results suggested that C allele might be associated with lesser negative symptom. More studies are needed to confirm these findings. In the future, we plan to study the associations between schizophrenia and other genetic polymorphisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
79Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Jul 156B: 536-45
PMID21598376
TitleHypomethylation of the serotonin receptor type-2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder.
AbstractSeveral lines of evidence indicate that dysfunction of serotonin signaling and HTR2A receptor are involved in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BD). DNA methylation of HTR2A at T102C polymorphic site influences HTR2A expression and aberrant DNA methylation of HTR2A promoter was reported in postmortem brain of patients with SCZ and BD. Hypothesizing that the brain's epigenetic alteration of HTR2A may also exist in peripheral tissues that can be used as a diagnostic/therapeutic biomarker, we analyzed HTR2A promoter DNA methylation in DNA extracted from the saliva of patients with SCZ and BD, and their first degree relatives versus normal controls. Bisulfite sequencing was used to screen DNA methylation status of the HTR2A promoter CpGs and qMSP was used to quantify the degree of cytosine methylation at differentially methylated sites. Most of the cytosines of the HTR2A promoter were unmethylated. However, CpGs of the -1438A/G polymorphism site, -1420 and -1223 were >95% methylated. The CpG at T102C polymorphic site and neighboring CpGs were ?70% methylated both in the patients and controls. qMSP analysis revealed that the cytosine of the T102C polymorphic site was significantly hypo-methylated in SCZ, BD, and their first degree relatives compared to the controls. Cytosine methylation of HTR2A at T102C polymorphic site in DNA derived from the saliva can potentially be used as a diagnostic, prognostic, and/or therapeutic biomarker in SCZ and BD. However, these preliminary observations need to be replicated in other populations with a larger sample size to be considered for clinical applications.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
80Schizophr. Res. 2011 Jul 129: 183-90
PMID21550210
TitleEpigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder.
AbstractHTR2A gene has been the subject of numerous studies in psychiatric genetics because LSD, which resembles serotonin causes psychosis and atypical antipsychotic drugs target the HTR2A receptor. However, evidence for the role of HTR2A polymorphism(s) in schizophrenia (SCZ) and bipolar disorder (BD) has been elusive. We hypothesized that epigenetic dysregulation of HTR2A may be involved in psycho-pathogenesis and analyzed promoter DNA methylome and expression of HTR2A in SCZ, BD and control subjects.
DNA derived from post-mortem brains of patients with SCZ and BD and matched control subjects (each 35) were obtained from the Stanley Medical Research Institute. While bisulfite DNA sequencing was used to screen and quantify cytosine methylation in the HTR2A promoter, corresponding gene expression was analyzed by qRT-PCR.
We found strong evidence for epigenetic fine-tuning of HTR2A expression. In general, the expression of HTR2A in individuals carrying the C allele of T102C (or G allele of -1438A/G polymorphism) was higher than TT genotype. Interestingly, promoter DNA of HTR2A was hypermethylated at and around the -1438A/G polymorphic site, but was hypomethylated at and around T102C polymorphic site in SCZ and BD compared to the controls. Furthermore, epigenetic down-regulation of HTR2A was associated with early age of disease onset in SCZ and BD.
Epigenetic dysregulation of HTR2A may contribute to SCZ, BD and earlier age of disease onset. Further research is required to delineate the dysregulation of other components of serotoninergic pathway to design new therapeutics based on the downstream effects of serotonin.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
81Behav. Genet. 2011 Sep 41: 709-15
PMID21399903
TitleEffect of serotonin-related gene polymorphisms on pathogenesis and treatment response in Korean schizophrenic patients.
AbstractSerotonin has been implicated in the pathophysiology of several psychiatric disorders including schizophrenia. Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. We aimed to investigate the associations of HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T variants with schizophrenia. A total of 202 patients with schizophrenia and 165 normal controls were genotyped for HTR1A C-1019G, HTR2A-1438A/G, TPH1 218A/C, and TPH2-703G/T single nucleotide polymorphisms (SNPs). In order to assess the severity of a patient's psychiatric symptoms, the brief psychiatric rating scale (BPRS), the positive and negative symptom scale (PANSS), and the Calgary depression scale for schizophrenia (CDSS) were administered. Genotype and allele frequencies were compared between groups via ?(2) statistics. Associations between the genotypes of candidate SNPs with the severity of symptoms were examined with ANOVA by comparing the mean scores of BPRS, PANSS, and CDSS according to genotype. No significant differences in the genotype distributions and allele frequencies of four SNPs were found between patients with schizophrenia and normal controls. There was a trend towards association of HTR1A C-1019G polymorphism with negative symptom. Negative symptom score of PANSS was lower in the patients with CC genotype than in the G allele carriers. These results suggested that C allele might be associated with lesser negative symptom. More studies are needed to confirm these findings. In the future, we plan to study the associations between schizophrenia and other genetic polymorphisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
82Mol. Psychiatry 2012 Sep 17: 887-905
PMID22584867
TitleConvergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.
AbstractWe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
83Zh Nevrol Psikhiatr Im S S Korsakova 2012 -1 112: 39-44
PMID23250597
Title[An association study of polymorphisms in HTR2A, BDNF and SLC6A4 genes with paranoid schizophrenia and suicidal behavior].
AbstractWe have developed a biochip for the analysis of candidate genes for schizophrenia. Using this biochip, allele and genotype frequencies for the polymorphisms of HTR2A, BDNF and SLC6A4 genes in 198 patients with schizophrenia and 192 healthy individuals have been obtained. The allele T of the HTR2A polymorphism rs6314 was identified as protective against the development of paranoid schizophrenia (p=0,014). An analysis of gene-gene interactions using the Multifactor-Dimensionality Reduction (MDR) algorithm has shown a statistically significant association of combined genotypes rs6311 G/-, rs6313 C/-, rs6314 C/C, rs7997012 G/- with the disease (p=0.019). Also it has been shown that the G/G genotype of the polymorphism rs6311 (p=0.013) and the C/C genotype of the polymorphism rs6313 (p=0.008) in the HTR2A gene are associated with the suicide attempt in schizophrenic patients. Correspondingly, an A allele, ?/- genotypes of the polymorphism rs6311 G>A and a T allele, T/- genotypes of the polymorphism rs6313 C>T were found to be less frequent in schizophrenic patients with a history of suicide attempt than in schizophrenic patients without a history of suicide attempt, thus suggesting their protective role in the development of suicidal behavior. The results confirm the hypothesis that the HTR2A plays an important role in the etiology of schizophrenia and suicidal behavior.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
84PLoS ONE 2012 -1 7: e36561
PMID22615781
TitleCandidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study.
AbstractFour 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
85Psychol Med 2012 Mar 42: 607-16
PMID21854684
TitleHypothesis-driven candidate genes for schizophrenia compared to genome-wide association results.
AbstractCandidate 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
86Pharmacogenomics J. 2012 Jun 12: 246-54
PMID21173788
TitlePharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia.
AbstractThe goal of this study was to identify genetic markers associated with LY2140023 monohydrate response in patients with schizophrenia. Variants in eight candidate genes related to the mechanism of action of LY2140023 or olanzapine were investigated in a genetic cohort collected from two clinical trials. Results from this genetic analysis indicate that 23 single nucleotide polymorphisms (SNPs) were associated with a change in Positive and Negative Syndrome Scale total score in response to LY2140023 at 28 days (P<0.01; false discovery rate <0.2). Sixteen of these SNPs were located in the serotonin 2A receptor (HTR2A). Bioinformatic analyses identified a putative antisense nested gene in intron 2 of HTR2A in the region of the genetic markers associated with LY2140023 response. These data suggest a genetic association exists between SNPs in several genes, such as HTR2A, and response to LY2140023 treatment. Additional clinical trials are needed to establish replication of these results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
87Aging Dis 2012 Aug 3: 291-300
PMID23185710
TitleAssociation of a Serotonin Receptor 2A Gene Polymorphism with Visual Sustained Attention in Early-Onset Schizophrenia Patients and their Non-Psychotic Siblings.
AbstractThe serotonin receptor 2A gene polymorphism is associated with attentional processes in schizophrenia. However, the specificity of the underlying cognitive constructs affected within this domain requires further elucidation. We carried out the first investigation of whether the TC/CC genotype of the 5-HT2A T102C polymorphism confers impairments in early-onset schizophrenia (EOS; onset of psychotic symptoms before age 18) but not in healthy siblings, the putative mechanism being that serotonergic inhibitory modulation of prefrontal dopamine is impaired in the presence of the C allele which in turn is a genetic risk marker for schizophrenia. Fifty-three EOS outpatients and 46 of their non-psychotic siblings (no current Axis I diagnoses) were genotyped for 5-HT2A T102C polymorphism. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptomatology severity. Diagnostic classification was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Structured Clinical Interview. The Degraded-Stimulus Continuous Performance Test (DS-CPT) was used to measure sustained focused attention. As predicted, EOS probands produced fewer correct responses (hit rate) and demonstrated poorer perceptual sensitivity compared with the healthy siblings. The C allele at codon 102 was associated with fewer correct responses compared with the TT genotype. There was no significant relationship between the polymorphism and clinical parameters, as measured using the PANSS. Our findings suggest that the C allele may be related to sustained attentional impairments in EOS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
88Transl Psychiatry 2012 -1 2: e113
PMID22832957
TitleAssociation between SNPs and gene expression in multiple regions of the human brain.
AbstractIdentifying the genetic cis associations between DNA variants (single-nucleotide polymorphisms (SNPs)) and gene expression in brain tissue may be a promising approach to find functionally relevant pathways that contribute to the etiology of psychiatric disorders. In this study, we examined the association between genetic variations and gene expression in prefrontal cortex, hippocampus, temporal cortex, thalamus and cerebellum in subjects with psychiatric disorders and in normal controls. We identified cis associations between 648 transcripts and 6725 SNPs in the various brain regions. Several SNPs showed brain regional-specific associations. The expression level of only one gene, PDE4DIP, was associated with a SNP, rs12124527, in all the brain regions tested here. From our data, we generated a list of brain cis expression quantitative trait loci (eQTL) genes that we compared with a list of schizophrenia candidate genes downloaded from the schizophrenia Forum (SZgene) database (http://www.szgene.org/). Of the SZgene candidate genes, we found that the expression levels of four genes, HTR2A, PLXNA2, SRR and TCF4, were significantly associated with cis SNPs in at least one brain region tested. One gene, SRR, was also involved in a coexpression module that we found to be associated with disease status. In addition, a substantial number of cis eQTL genes were also involved in the module, suggesting eQTL analysis of brain tissue may identify more reliable susceptibility genes for schizophrenia than case-control genetic association analyses. In an attempt to facilitate the identification of genetic variations that may underlie the etiology of major psychiatric disorders, we have integrated the brain eQTL results into a public and online database, Stanley Neuropathology Consortium Integrative Database (SNCID; http://sncid.stanleyresearch.org).
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
89Mol Cytogenet 2012 -1 5: 2
PMID22214315
TitleIsochromosome 13 in a patient with childhood-onset schizophrenia, ADHD, and motor tic disorder.
AbstractA small percentage of all cases of schizophrenia have a childhood onset. The impact on the individual and family can be devastating. We report the results of genetic analyses from a patient with onset of visual hallucinations at 5 years, and a subsequent diagnosis at 9 years of schizophrenia, attention deficit hyperactivity disorder (ADHD) with hyperactivity and impulsivity, and chronic motor tic disorder.
Karyotypic analysis found 45,XX,i(13)(q10) in all cells examined. Alpha satellite FISH of isochromosome 13 revealed a large unsplit centromeric region, interpreted as two centromeres separated by minimal or undetectable short-arm material or as a single monocentric centromere, indicating that the isochromosome likely formed post-zygotically by a short arm U-type or centromeric exchange. Characterization of chromosome 13 simple tandem repeats and Affymetrix whole-genome 6.0 SNP array hybridization found homozygosity for all markers, and the presence of only a single paternal allele in informative markers, consistent with an isodisomic isochromosome of paternal origin. Analysis of two chromosome 13 schizophrenia candidate genes, D-amino acid oxidase activator (DAOA) and 5-hydroxytryptamine (serotonin) receptor 2A (5-HTR2A), failed to identify non-synonymous coding mutations but did identify homozygous risk polymorphisms.
We report a female patient with childhood-onset schizophrenia, ADHD, and motor tic disorder associated with an isodisomic isochromosome 13 of paternal origin and a 45,XX,i(13)(q10q10) karyotype. We examined two potential mechanisms to explain chromosome 13 involvement in the patient's pathology, including reduction to homozygosity of a paternal mutation and reduction to homozygosity of a paternal copy number variation, but were unable to identify any overtly pathogenic abnormality. Future studies may consider whether epigenetic mechanisms resulting from uniparental disomy (UPD) and the lack of chromosome 13 maternal alleles lead to the patient's features.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
90Zh Nevrol Psikhiatr Im S S Korsakova 2012 -1 112: 39-44
PMID23250597
Title[An association study of polymorphisms in HTR2A, BDNF and SLC6A4 genes with paranoid schizophrenia and suicidal behavior].
AbstractWe have developed a biochip for the analysis of candidate genes for schizophrenia. Using this biochip, allele and genotype frequencies for the polymorphisms of HTR2A, BDNF and SLC6A4 genes in 198 patients with schizophrenia and 192 healthy individuals have been obtained. The allele T of the HTR2A polymorphism rs6314 was identified as protective against the development of paranoid schizophrenia (p=0,014). An analysis of gene-gene interactions using the Multifactor-Dimensionality Reduction (MDR) algorithm has shown a statistically significant association of combined genotypes rs6311 G/-, rs6313 C/-, rs6314 C/C, rs7997012 G/- with the disease (p=0.019). Also it has been shown that the G/G genotype of the polymorphism rs6311 (p=0.013) and the C/C genotype of the polymorphism rs6313 (p=0.008) in the HTR2A gene are associated with the suicide attempt in schizophrenic patients. Correspondingly, an A allele, ?/- genotypes of the polymorphism rs6311 G>A and a T allele, T/- genotypes of the polymorphism rs6313 C>T were found to be less frequent in schizophrenic patients with a history of suicide attempt than in schizophrenic patients without a history of suicide attempt, thus suggesting their protective role in the development of suicidal behavior. The results confirm the hypothesis that the HTR2A plays an important role in the etiology of schizophrenia and suicidal behavior.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
91Acta Neuropsychiatr 2013 Dec 25: 342-8
PMID25287874
TitleAssociation of schizophrenia with T102C (rs6313) and 1438 A/G (rs6311) polymorphisms of HTR2A gene.
AbstractThe aim of this study is to investigate whether there were any associations between the T102C and 1438 A/G polymorphisms of the 5-HT2A receptor gene and schizophrenia. We conducted a case-control study of the T102C and 1438 A/G polymorphisms in Turkish patients.
We compared genotypes and allele frequencies of T102C and 1438 A/G polymorphisms of 5-HT2A receptor gene in 102 patients with schizophrenia diagnosed, according to DSM-IV, and 107 healthy controls. Genotyping was performed by real-time polymerase chain reaction.
We found no significant association between schizophrenia and genotypic or allele frequencies of HTR2A gene 102T/C (rs6313) and 1438 A/G (6311) polymorphisms. However, comparison of HTR2A gene 102 T/C and 1438 A/G polymorphisms in terms of genotypic and allele frequencies between the two patient groups, with or without a family history of schizophrenia, shows that T- and A-allele frequencies were significantly higher (p < 0.05) in the case group that has a history of schizophrenia in their family.
In conclusion, our results do not support the hypothesis that the T102C and 1438 A/G polymorphisms in the 5-HT2A receptor gene are associated with schizophrenia, but further studies in a larger sample are needed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
92Asia Pac Psychiatry 2013 Mar 5: 24-30
PMID23857788
TitleT102C polymorphism of serotonin 2A type receptor gene confers susceptibility to (early onset) schizophrenia in Han Chinese: an association study and meta-analysis.
AbstractSeveral lines of evidence have indicated that serotonin 2A receptor (HTR2A) may be involved in the pathophysiology of schizophrenia. One functional polymorphism in HTR2A (T102C) has been widely investigated; however, the results have been inconsistent. The purpose of this study was to evaluate the association between HTR2A T02C polymorphism and schizophrenia in a Chinese Han population.
We performed a case-control study, using an early onset sample, which may be an attractive subgroup for genetic studies. In addition, we performed a meta-analysis of the combined sample groups in Han Chinese.
Our study, based on 385 schizophrenic patients and 399 controls, found a significant genotype-wise association of T102C and schizophrenia (P = 0.02). After applying stratified analyses, the dominant model for T allele produced significant association (OR = 1.60, 95%CI = 1.11-2.30, P = 0.01). In the meta-analysis including all of the published population-based association studies in Han Chinese and the present association study, the pooled genotype-wise result in a dominant model was statistically significant with a summary OR of 1.25 (95%CI = 1.04-1.50, P = 0.02).
Our results suggest that the HTR2A T102C polymorphism may confer susceptibility to schizophrenia in Han Chinese.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
93J. Neurosci. Res. 2013 May 91: 623-33
PMID23404241
TitleHTR2A-1438A/G polymorphism influences the risk of schizophrenia but not bipolar disorder or major depressive disorder: a meta-analysis.
AbstractThe incidence of psychiatric disorders has been shown to have a strong genetic component, and we conducted this study to investigate whether the -1438A/G polymorphism of the HTR2A gene was associated with susceptibility to schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Pooled odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using data obtained from a total 27 studies that investigated an association between the HTR2A -1438A/G polymorphism and SZ (15), BD (7), and MDD (4). We failed to observe an association between the HTR2A -1438A/G polymorphism and BD and MDD, and we found contrary results with regard to SZ. Our results showed that the -1438A/G polymorphism was a risk factor for SZ, especially in Caucasians (allele model: OR, 1.12; 95% CI, 1.05-1.20; I(2) = 17.3%; dominant model: OR, 1.14; 95% CI, 1.03-1.27; I(2) = 15.3%; recessive model: OR, 1.20; 95% CI, 1.06-1.37; I(2) = 0.0%; codominant model 1: OR, 1.16; 95% CI, 1.01-1.32; I(2) = 0.0%). We found that the association of the HTR2A -1438A/G polymorphism with SZ depends on the ethnic origin of the study population, and this genetic variant does not modify the susceptibility to BD or MDD. 2013 Wiley Periodicals, Inc.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
94Int Rev Psychiatry 2013 Oct 25: 509-33
PMID24151799
TitleClinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy.
AbstractAdverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
95Asia Pac Psychiatry 2013 Mar 5: 24-30
PMID23857788
TitleT102C polymorphism of serotonin 2A type receptor gene confers susceptibility to (early onset) schizophrenia in Han Chinese: an association study and meta-analysis.
AbstractSeveral lines of evidence have indicated that serotonin 2A receptor (HTR2A) may be involved in the pathophysiology of schizophrenia. One functional polymorphism in HTR2A (T102C) has been widely investigated; however, the results have been inconsistent. The purpose of this study was to evaluate the association between HTR2A T02C polymorphism and schizophrenia in a Chinese Han population.
We performed a case-control study, using an early onset sample, which may be an attractive subgroup for genetic studies. In addition, we performed a meta-analysis of the combined sample groups in Han Chinese.
Our study, based on 385 schizophrenic patients and 399 controls, found a significant genotype-wise association of T102C and schizophrenia (P = 0.02). After applying stratified analyses, the dominant model for T allele produced significant association (OR = 1.60, 95%CI = 1.11-2.30, P = 0.01). In the meta-analysis including all of the published population-based association studies in Han Chinese and the present association study, the pooled genotype-wise result in a dominant model was statistically significant with a summary OR of 1.25 (95%CI = 1.04-1.50, P = 0.02).
Our results suggest that the HTR2A T102C polymorphism may confer susceptibility to schizophrenia in Han Chinese.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
96JAMA Psychiatry 2013 Sep 70: 921-30
PMID23842608
TitleConverging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment.
AbstractSerotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with physiologic as well as behavioral effects.
To use a hierarchical approach to determine the functional effects of this single-nucleotide polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with genetic risk for schizophrenia, and on treatment with olanzapine.
In silico predictions, in vitro, and case-control investigations.
Academic and clinical facilities.
The postmortem study included 112 brains from healthy individuals; the in vivo investigation included a total sample of 371 healthy individuals and patients with schizophrenia. EXPOSURES Patients received olanzapine monotherapy for 8 weeks.
In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine treatment in patients with schizophrenia.
Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro, inefficient prefrontal blood oxygen level-dependent functional magnetic resonance imaging response during working memory and attentional control processing, and impaired working memory and attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine treatment.
Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment with olanzapine.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
97Indian J. Med. Res. 2014 Dec 140: 713-5
PMID25758569
TitleAn insight into the understanding of 5-HTR2A variants leading to schizophrenia.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
98J. Cell. Biochem. 2014 Dec 115: 2065-72
PMID25043477
TitleThe developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes.
AbstractThe serotonin receptor 5-HT2A (encoded by HTR2A) is an important regulator of fetal brain development and adult cognitive function. Environmental signals that induce epigenetic changes of serotonin response genes, including HTR2A, have been implicated in adverse mental health outcomes. The objective of this perspective article is to address the medical implications of HTR2A epigenetic regulation, which has been associated with both infant neurobehavioral outcomes and adult mental health. Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes. Epigenetic regulation of HTR2A has been studied in several different types of tissues, including the placenta. The placenta is an important source of serotonin during fetal neurodevelopment, and placental epigenetic variation of HTR2A has been associated with infant neurobehavioral outcomes, which may represent the basis of adult mental health disorders. Further analysis is needed to identify intrinsic and extrinsic factors that modulate HTR2A methylation, and the mechanism by which this epigenetic variation influences fetal growth and leads to altered brain development, manifesting in psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
99BMC Psychiatry 2014 -1 14: 351
PMID25539791
TitleA Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia.
AbstractPomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia.
Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2weeks prior to study entry. Patients (N?=?1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2mg BID for 6weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461.
Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p?=?.154 [0.01]; LY80, p?=?.698 [0.01], subpopulation: LY40, p?=?.033 [0.0025]; LY80, p?=?.659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p?LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed.
A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR schizophreniaClinicalTrials.gov identifier: NCT01086748.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
100BMC Psychiatry 2014 -1 14: 351
PMID25490958
TitleA double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia.
AbstractPomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia.
Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N = 1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461.
Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p = .154 [0.01]; LY80, p = .698 [0.01], subpopulation: LY40, p = .033 [0.0025]; LY80, p = .659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p < .001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023.
LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed.
A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR schizophrenia ClinicalTrials.gov identifier: NCT01086748 .
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
101Neurosci. Lett. 2014 Mar 563: 123-8
PMID24491429
TitleComprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin.
AbstractBlonanserin 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
102Neuropharmacology 2014 Nov 86: 311-8
PMID25150943
TitleEvaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: effect of antidepressant treatment.
AbstractSeveral studies have demonstrated alterations in serotonin 5-HT2A (5-HT2AR) and glutamate metabotropic mGlu2 (mGlu2R) receptors in depression, but never in the same sample population. Recently it has been shown that both receptors form a functional receptor heterocomplex that is altered in schizophrenia. The present study evaluates the gene expression and protein density of 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder (n=14) compared with control subjects (n=14) in a paired design. No significant differences between subjects with depression and controls in the relative mRNA levels of the genes HTR2A, GRM2 and GRM3 were observed. The 5-HT2AR density evaluated by [(3)H]ketanserin binding was significantly lower in antidepressant-treated subjects (Bmax=31317fmol/mg protein; p<0.05) compared to controls (Bmax=36012fmol/mg protein) but not in antidepressant-free subjects (Bmax=39416fmol/mg protein; p>0.05). In rats, chronic treatment with citalopram (10mg/kg/day) and mirtazapine (5mg/kg/day) decreased mRNA expression and 5-HT2AR density whereas reboxetine (20mg/kg/day) modified only mRNA expression. The mGlu2/3R density evaluated by [(3)H]LY341495 binding was not significantly different between depression and control subjects. The present results demonstrate no changes in expression and density of both 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder under basal conditions. However, antidepressant treatment induces a decrease in 5-HT2AR density. This finding suggests that 5-HT2AR down-regulation may be a mechanism for antidepressant effect.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
103Schizophr. Res. 2014 Feb 152: 373-80
PMID24411530
TitleDNA hypermethylation of serotonin transporter gene promoter in drug nave patients with schizophrenia.
AbstractDysfunctional serotonin signaling has been linked to the pathogenesis of autism, obsessive compulsive disorder, mood disorders and schizophrenia. While the hypo-activity of serotonin signaling is involved in the pathogenesis of depression, anxiety and obsessive compulsive disorder; LSD, an agonist of serotonin type 2 receptor (5-HTR2A) induces psychosis. Therefore, anxiety and depressive disorders are treated by SSRIs which inhibit serotonin transporter (5-HTT) while psychotic disorders are controlled by drugs that block serotonin and/or dopamine receptors. Since genetic polymorphisms and epigenetic dysregulation of 5-HTT are involved in the pathogenesis of mental diseases, we analyzed DNA methylation of 5-HTT promoter in post-mortem brains and saliva samples of patients with schizophrenia (SCZ) and bipolar disorder (BD) to evaluate its potential application as a diagnostic and/or therapeutic biomarker in SCZ and BD.
Whole genome DNA methylation profiling was performed for a total of 24 samples (including two saliva samples) using the Illumina 27K (for 12 samples) and 450K DNA methylation array platform (for another 12 samples), followed by bisulfite sequencing to identify candidate CpGs for further analysis. Quantitative methylation specific PCR (qMSP) was used to assess the degree of CpG methylation of 5-HTT promoter in 105 post-mortem brains (35 controls, 35 SCZ and 35 BD) and 100 saliva samples (30 controls, 30 SCZ, 20 BD and 20 first degree relatives of SCZ or BD). The U133 2.0 Plus Human Transcriptome array for a total of 30 post-mortem brain samples (each group 10) followed by quantitative real-time PCR was used to study 5-HTT expression in 105 post-mortem brain samples.
The qMSP analysis for 5-HTT promoter region showed DNA hypermethylation in post-mortem brain samples of SCZ patients (~30%), particularly in drug free patients (~60%, p=0.04). Similarly, there was a trend for DNA hypermethylation in antipsychotic free BD patients (~50%, p=0.066). qMSP analysis of DNA extracted from the saliva samples also exhibited hypermethylation of 5-HTT promoter in patients with SCZ (~30%, p=0.039), which was more significant in drug nave SCZ patients (>50%, p=0.0025). However, the difference was not significant between the controls and unaffected first degree relatives of patients with SCZ (p=0.37) and versus patients using antipsychotic drugs (p=0.2). The whole genome transcriptome analysis of post-mortem brain samples showed reduced expression of 5-HTT in SCZ compared to the control subjects (~50%, p=0.008), confirmed by quantitative real-time PCR analysis (~40%, p=0.035) which was more significant in drug free SCZ patients (~70%, p=0.022).
A correlation between reduction in 5-HTT expression and DNA hypermethylation of the 5-HTT promoter in drug nave SCZ patients suggests that an epigenetically defined hypo-activity of 5-HTT may be linked to SCZ pathogenesis. Furthermore, this epigenetic mark in DNA extracted from saliva can be considered as one of the key determinants in a panel of diagnostic and/or therapeutic biomarkers for SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
104Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014 Jul 165B: 438-55
PMID24962835
TitleAssociation of the T102C polymorphism in the HTR2A gene with major depressive disorder, bipolar disorder, and schizophrenia.
AbstractA number of studies have assessed a relationship between the T102C polymorphism in the HTR2A gene with an increased risk of major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ). However, the results have been inconsistent. Hence, we performed this study to further evaluate potential associations between the T102C polymorphism and MDD, BPD, and SCZ. The strength of separate associations between the T102C polymorphism and the risk of MDD, BPD, or SCZ was measured by ORs and 95% confidence intervals (CIs) in six genetic models. Cochran's chi-square-based Q-statistic and I(2) were used to evaluate the heterogeneity between studies. The funnel plot and the Egger's test were used to assess the publication bias. Cumulative meta-analysis was also performed to evaluate the trend in OR over time. No significant association was found in the overall analysis of MDD, BPD and SCZ with a sample size of 17,178 cases and 20,855 control subjects. In a further analysis by ethnicity, the OR and 95% CIs indicated the T102C polymorphism was not associated with MDD, BPD, or SCZ in Caucasian, Asian or Chinese populations. No publication bias was observed in the meta-analysis, and the cumulative analyses indicated the robust stability of the results. Thus, the results of our study indicate that the T102C polymorphism is not associates with increased susceptibility to MDD, BPD, and SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
105Int. J. Neuropsychopharmacol. 2014 Jun 17: 895-906
PMID24495390
TitleLower cortical serotonin 2A receptors in major depressive disorder, suicide and in rats after administration of imipramine.
AbstractWe have attempted to replicate studies showing higher levels of serotonin 2A receptors (HTR2A) in the cortex of people with mood disorders and to determine the effects of treating rats with antidepressant drugs on levels of that receptor. In situ [3H]ketanserin binding and autoradiography was used to measure levels of HTR2A in Brodmann's area (BA) 46 and 24 from people with major depressive disorders (MDD, n = 16), bipolar disorders (BD, n = 14) and healthy controls (n = 14) as well as the central nervous system (CNS) of rats (20 per treatment arm) treated for 10 or 28 d with fluoxetine (10 mg/kg/d) or imipramine (20 mg/kg/d). Compared with controls, HTR2A were lower in BA 24, but not BA 46, from people with MDD (p = 0.005); HTR2A were not changed in BD. Levels of HTR2A were lower in BA 24 (p = 0.007), but not BA 46, from people who had died by suicide. Finally, levels of HTR2A were lower in the CNS of rats treated with imipramine, but not fluoxetine, for 28 d, but not 10 d. From our current and previous data we conclude cortical HTR2A are lower in schizophrenia, MDD, people with mood disorders who died by suicide, rats treated with some antipsychotic or some antidepressant drugs. As levels of cortical HTR2A can be affected by the aetiologies of different disorders and mechanisms of action of different drugs, a better understanding of how such changes can occur needs to be elucidated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
106ACS Chem Neurosci 2015 Jul 6: 1137-42
PMID25857407
TitleHtr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner.
AbstractPharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor. To determine if acute stress alters 5-HT2AR expression, we examined the effect of sleep deprivation on cortical HTR2A mRNA in mice. We found that 6 h of sleep deprivation induces a twofold increase in HTR2A mRNA, a more rapid effect than has been previously reported. This effect requires the immediate early gene early growth response 3 (Egr3), as sleep deprivation failed to induce HTR2A expression in Egr3-/- mice. These findings provide a functional link between two schizophrenia candidate genes and an explanation of how environment may influence a genetic predisposition for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
107Neuropsychopharmacology 2015 Jun 40: 1600-8
PMID25563748
TitleVariation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics.
AbstractDopamine 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
108Psychiatr. Genet. 2015 Aug 25: 168-77
PMID26075944
TitleAssociation of the HTR2A 102T/C polymorphism with attempted suicide: a meta-analysis.
AbstractAn association between the serotonin 2A receptor (5-HT2A receptor) gene and suicidal behavior has been reported in many studies. However, no consistent conclusion has been reached. One potential reason for this is heterogeneity in the studies analyzed, which may have been caused by the selection of different types of cases and controls. In the present study, we pooled data from the previous published papers to clarify the association between HTR2A 102T/C and attempted suicide. All case-control studies written in English and published up until 20 November 2013 were selected. The history of suicide attempts and other relevant data were extracted. According to the findings of previous studies, the recessive model was used to evaluate the role of genotype in attempted suicide. We divided the patients into three groups on the basis of the history of suicide attempts and mental disorder. Genotype distribution of the suicide attempters was compared with normal controls and patients with mental disorder, respectively. There were no significant differences in 5-HT2A receptor 102T/C genotype distributions between those who attempted suicide and the normal controls, and the results were similar for the comparisons with mental disorder patient controls. When subgroup analysis of the types of mental disorder was carried out, all heterogeneity disappeared and effect sizes increased. A significant association was observed for the schizophrenia disorder subgroup (odds ratio=1.73; 95% confidence interval: 1.11-2.69). Our meta-analysis does not support the previously suggested association between HTR2A 102T/C and attempted suicide in the general population. However, in patients with schizophrenia, the C/C genotype of 5-HT2A receptor 102T/C may increase the risk of attempted suicide. The heterogeneity in relevant studies may have been caused by the characteristic variety of mixed mental disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
109Curr. Pharm. Des. 2015 -1 21: 3788-96
PMID26044978
TitleWhen is a Proof-of-Concept (POC) not a POC? Pomaglumetad (LY2140023) as a Case Study for Antipsychotic Efficacy.
AbstractPomaglumetad methionil (LY2140023) is a mGlu2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. While there was some evidence of an antipsychotic effect in these studies on an a priori specified genetically-defined subpopulation based on single nucleotide polymorphisms of the 5-hydroxytryptamine2A receptor gene (HTR2A) , these effects were modest when compared to very limited effects in the overall population of schizophrenic patients responding to SOC second generation antipsychotic drugs. Post-hoc analyses also suggested antipsychotic efficacy for pomaglumetad methionil in subjects with a disease duration equal/less than 3 years or subjects previously treated with antipsychotic drugs predominantly acting at dopamine D2 receptors compared to 5-HT2A receptors. Orthogonal to these results with the mGlu2/3 receptor agonist prodrug, a 5-HT2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson's disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu2/3 receptor agonists and 5-HT2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer's disease psychosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
110Neuropathol. Appl. Neurobiol. 2015 Jun 41: 520-32
PMID25041420
TitleRegion-specific regulation of the serotonin 2A receptor expression in development and ageing in post mortem human brain.
AbstractThe serotonin 2A receptor (HTR2A) is widely expressed in the brain and involved in the modulation of fear, mood, anxiety and other symptoms. HTR2A and HTR2A gene variations are implicated in depression, schizophrenia, anxiety and obsessive-compulsive disorder. To understand HTR2A signalling changes in psychiatric or neurodegenerative disorders, its normal pattern of brain expression and region specificity during development and ageing needs to be clarified. The aim of the present study was to assess HTR2A expression through developmental and ageing stages in six brain regions in post mortem human brain samples from individuals with no clinical or neuropathological evidence of neuropsychiatric disorders and to investigate the interaction with the rs6311 HTR2A promoter polymorphism.
DNA, RNA and protein were isolated from post mortem brain samples including six regions (frontal cortex, striatum, amygdala, thalamus, brain stem and cerebellum) from 55 individuals. HTR2A mRNA levels were assessed using quantitative real-time RT-PCR and HTR2A protein levels - with Western blot. The rs6311 HTR2A polymorphism was analysed with genotyping.
We found that HTR2A mRNA and protein levels are differentially regulated with age in different brain regions studied, but are not affected by gender. Significant changes in HTR2A expression with age were found in frontal cortex, amygdala, thalamus, brain stem and cerebellum.
Our results show plasticity and region specificity of HTR2A expression regulation in human brain with age, which may be important for the interaction with other neurotransmitter systems and for the occurrence of developmental periods with increased vulnerability to neuropsychiatric or neurodegenerative disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
111Curr. Pharm. Des. 2015 -1 21: 3788-96
PMID26044978
TitleWhen is a Proof-of-Concept (POC) not a POC? Pomaglumetad (LY2140023) as a Case Study for Antipsychotic Efficacy.
AbstractPomaglumetad methionil (LY2140023) is a mGlu2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. While there was some evidence of an antipsychotic effect in these studies on an a priori specified genetically-defined subpopulation based on single nucleotide polymorphisms of the 5-hydroxytryptamine2A receptor gene (HTR2A) , these effects were modest when compared to very limited effects in the overall population of schizophrenic patients responding to SOC second generation antipsychotic drugs. Post-hoc analyses also suggested antipsychotic efficacy for pomaglumetad methionil in subjects with a disease duration equal/less than 3 years or subjects previously treated with antipsychotic drugs predominantly acting at dopamine D2 receptors compared to 5-HT2A receptors. Orthogonal to these results with the mGlu2/3 receptor agonist prodrug, a 5-HT2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson's disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu2/3 receptor agonists and 5-HT2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer's disease psychosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
112Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Apr 171: 325-32
PMID26616111
TitleDisorder-specific genetic factors in obsessive-compulsive disorder: A comprehensive meta-analysis.
AbstractMuch remains to be learned about the etiology of obsessive-compulsive disorder (OCD). Twin studies suggest that it arises from both disorder-specific and non-specific genetic factors. To understand the etiology of OCD per se, it is necessary to identify disorder-specific factors. Previous research shows that OCD is associated with serotonin-related polymorphisms (5-HTTLPR coded as triallelic and HTR2A rs6311/rs6313) and, in males, a polymorphism involved in catecholamine modulation; COMT (rs4680). The present study is the first comprehensive meta-analysis to investigate whether these polymorphisms are specific to OCD. A meta-analysis was conducted for genetic association studies of OCD or any other psychiatric disorder, published in any language, in any country. A total of 551 studies were examined, of which 290 were included, consisting of 47,358 cases and 68,942 controls from case control studies, and 2,443 trios from family based studies. The main meta-analysis was limited to those disorders in which there were at least five datasets (studies or sub-studies) per disorder. Results confirmed that OCD is associated with polymorphisms of 5-HTTLPR, HTR2A, and, in males only, COMT. These polymorphisms were not associated with almost all other forms of psychopathology, including unipolar mood disorders, bipolar disorder, panic disorder, schizophrenia, and alcohol dependence. OCD, compared to most other disorders, had a significantly stronger association with particular alleles of each of the polymorphisms. Results did not differ across ancestral groups (Asian vs. Caucasian), designs (case control vs. family based), or diagnostic systems. Results suggest that the polymorphisms investigated in this study are relatively specific to OCD. 2015 Wiley Periodicals, Inc.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
113Brain Behav. Immun. 2016 Jan 51: 119-30
PMID26254231
TitleDisruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration.
AbstractThe pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second-generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (Htr1a, HTR2A, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
114J Pers Med 2016 -1 6: -1
PMID26861400
TitleSerotonin 2A Receptor SNP rs7330461 Association with Treatment Response to Pomaglumetad Methionil in Patients with Schizophrenia.
AbstractThis study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with pomaglumetad methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to pomaglumetad methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ? 0.05) greater improvement in Positive and Negative Syndrome Scale (PANSS) total scores during treatment with pomaglumetad methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving pomaglumetad methionil had significantly (p ? 0.05) greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC) treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to pomaglumetad methionil compared to the A/A genotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
115Neuropsychobiology 2016 -1 73: 10-5
PMID26812280
TitleInteraction between Methylation and CpG Single-Nucleotide Polymorphisms in the HTR2A Gene: Association Analysis with Suicide Attempt in Schizophrenia.
AbstractDysfunctional mechanisms in the serotonergic system have been implicated in suicidal behavior among patients with schizophrenia. However, previous association analyses of major serotonin genes have provided inconsistent findings regarding their role in suicidal behavior. The goal of the current study was to identify single-nucleotide polymorphisms (SNP) within HTR2A that directly affect CpG methylation sites in schizophrenic patients with suicidal behavior. Furthermore, direct methylation analysis was performed using genomic DNA from peripheral leukocytes employing bisulfite pyrosequencing to assess the contributions of six CpG sites in HTR2A exon I in 67 schizophrenia patients assessed for lifetime suicide attempt. Potential methylation in 25 CpG SNPs across the entire HTR2A gene was analyzed considering their direct contribution to methylation. When we compared direct methylation between attempters and nonattempters, we found that only the polymorphic T102C (rs6313) was significantly different between the two groups (p = 0.02). Furthermore, in the potential methylation analysis, we found a nominal association with suicide attempt for six of the 25 SNPs analyzed, i.e. rs2770293 (p = 0.045), rs6313 (p = 0.033), rs17068986 (p = 0.029), rs4942578 (p = 0.024), rs1728872 (p = 0.014), and rs9534511 (p = 0.003). The results of this investigation provide preliminary evidence that the combined analysis of CpG SNPs and methylation may be useful for investigating the genetic and epigenetic factors involved in suicidal behavior.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
116Brain Behav. Immun. 2016 Jan 51: 119-30
PMID26254231
TitleDisruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration.
AbstractThe pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second-generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (Htr1a, HTR2A, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
117Neuropsychobiology 2016 -1 73: 10-5
PMID26812280
TitleInteraction between Methylation and CpG Single-Nucleotide Polymorphisms in the HTR2A Gene: Association Analysis with Suicide Attempt in Schizophrenia.
AbstractDysfunctional mechanisms in the serotonergic system have been implicated in suicidal behavior among patients with schizophrenia. However, previous association analyses of major serotonin genes have provided inconsistent findings regarding their role in suicidal behavior. The goal of the current study was to identify single-nucleotide polymorphisms (SNP) within HTR2A that directly affect CpG methylation sites in schizophrenic patients with suicidal behavior. Furthermore, direct methylation analysis was performed using genomic DNA from peripheral leukocytes employing bisulfite pyrosequencing to assess the contributions of six CpG sites in HTR2A exon I in 67 schizophrenia patients assessed for lifetime suicide attempt. Potential methylation in 25 CpG SNPs across the entire HTR2A gene was analyzed considering their direct contribution to methylation. When we compared direct methylation between attempters and nonattempters, we found that only the polymorphic T102C (rs6313) was significantly different between the two groups (p = 0.02). Furthermore, in the potential methylation analysis, we found a nominal association with suicide attempt for six of the 25 SNPs analyzed, i.e. rs2770293 (p = 0.045), rs6313 (p = 0.033), rs17068986 (p = 0.029), rs4942578 (p = 0.024), rs1728872 (p = 0.014), and rs9534511 (p = 0.003). The results of this investigation provide preliminary evidence that the combined analysis of CpG SNPs and methylation may be useful for investigating the genetic and epigenetic factors involved in suicidal behavior.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias