Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distribution of the Msp I and Bal I genotypes were not independent in 297 individuals (chi 2 = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism (chi 2 = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls (chi 2 = 5.3, df = 1, P = 0.02) and found more important in mal than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls (chi 2 = 0.06, df = 1, P = 0.80, chi 2 = 0.22, df = 1, P = 0.90 and chi 2 = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3' part of the gene may explain the discrepant results obtained with the two polymorphisms.
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PMID:Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia. 867 17

Using a case-control design, an association of schizophrenia with the dopamine D3 receptor gene (D3RG) locus was investigated. Initial analysis of pooled results from published studies revealed a significant excess of individuals homozygous for either allele among the patients. The association was next tested in two cohorts ascertained independently at Pittsburgh, Pennsylvania and at Houston, Texas. The Pittsburgh sample was comprised of patients with schizophrenia (DSM-III-R) (n = 130). The controls belonged to two groups: adults screened for the absence of substance abuse or major psychiatric illness (n = 128), and neonates (n = 160). Multivariate analysis suggested an association with allele 1 of the biallelic D3RG polymorphism in comparison with the adult, but not the neonatal, controls. The association was most marked among Caucasian patients with a family history of schizophrenia (odds ratio 13.69, confidence intervals 1.80, 104.30). Survival analysis suggested an earlier age of onset among male patients homozygous for allele 2. The Houston cohort included Caucasian patients with schizophrenia or schizoaffective disorder (DSM-III-R criteria, n = 50), and normal controls matched for gender (n = 51). In this group, no significant associations were noted among all the patients or among subgroups of patients based on family history or age of onset. Possible reasons for the discordant results are discussed.
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PMID:Association study of schizophrenia and the dopamine D3 receptor gene locus in two independent samples. 895 Apr 7

Two molecular-genetic markers-H-ras and YNH24 (chromosome 2)-were tested for genetic linkage with schizophrenia in eight Russian families with different forms of the disease. Thirty-nine subjects, including 13 affected ones, were examined. Five alleles represented as DNA fragments from 2.4 to 4.0 kb in size were detected in DNA samples from probands and other family members when the H-ras probe and TagI restriction endonuclease were used. Eleven alleles were identified in hybridization experiments with YNH24 as a probe. Linkage tests between marker alleles and the schizophrenia predisposition gene were performed by means of the sib-pair method. Statistically significant evidence (5% significance level) for linkage between allele 2 of H-ras and the gene controlling predisposition to schizophrenia was found.
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PMID:[Linkage analysis of schizophrenia with markers of chromosomes 2 and 11 in russian families]. 896 84

Association of the dopamine D3 receptor gene (DRD3) and schizophrenia was examined in unrelated Israeli and Italian schizophrenic patients and ethnically matched normal control subjects. In the combined sample, there was a significant excess of DRD3 allele 2 among the schizophrenic patients (chi2 = 4.70, d.f. 1, p = 0.03). Comparison of genotype frequencies revealed an excess of the 2-2 genotype in the combined schizophrenic sample (chi2 = 8.30, d.f. 1, p = 0.01) and in the non-Ashkenazi Israeli schizophrenics alone (chi2 = 5.70, d.f. 2, p = 0.05). DRD3 2-2 genotype conferred a significantly increased risk of schizophrenia (chi2 = 8.21, d.f. 1, p = 0.004; OR = 2.87, CI 95% = 1.36-5.76) in the combined sample and in the non-Ashkenazi Israeli schizophrenics (chi2 = 7.22, d.f. 1, p = 0.04; OR = 7.22, CI 95% = 1.04-24.83). In the combined and Italian samples, allele 2 was associated with early age of onset as was the 2-2 genotype in the combined sample and non-Ashkenazi group. The 2-2 genotype was associated with poor response to neuroleptics, particularly in the non-Ashkenazi, Israeli schizophrenics. The possibility that DRD3 or a locus in linkage disequilibrium with it may play a role in the transmission of schizophrenia, is considered in relation to previous positive and negative reports.
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PMID:Evidence for an association between the dopamine D3 receptor gene DRD3 and schizophrenia. 901 73

Schizophrenia is a serious psychiatric illness with a life-time risk of approximately one percent. Many of the patients, but not all, benefit from treatment with anti-psychotic drugs known to block dopamine D2-like receptors. The use of conventional neuroleptics is, however, hampered by the risk of extrapyramidal side-effects. Tardive dyskinesia (TD) is usually regarded as the most serious of these drug-induced movement disorders due to its high prevalence and potentially irreversible nature. In this study, we have investigated the genetic variation of the dopamine D3 receptor gene (DRD3) as a putative risk factor for TD in schizophrenic patients receiving long-term anti-psychotic drug therapy. We found a high frequency (22-24%) of homozygosity for the Ser9Gly variant (allele 2) of the DRD3 gene among subjects with TD in both a cross-sectional and a longitudinal evaluation, as compared with the relative under-representation (4-6%) of this genotype in patients with no or fluctuating TD. This result indicates that autosomal inheritance of two polymorphic Ser9Gly alleles (2-2 genotype), but not homozygosity for the wild-type allele (1-1 genotype), is a susceptibility factor for the development of TD, an observation which may improve the understanding of the pathophysiological mechanisms of TD and influence the design and choice of future anti-psychotic drugs. The correlation between a serious motor side-effect and a genetic marker could lead to selection bias in the sampling of schizophrenic patients for genetic studies, and may therefore explain the apparent association reported between susceptibility for schizophrenia per se and homozygosity for the DRD3 gene.
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PMID:Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. 910 22

Recent findings of an association between schizophrenia and a T102C polymorphism at the 5-HT2a receptor gene (particularly with genotype 1-2 and 2-2 and allele 2) prompted us to investigate this marker in familial Irish schizophrenic patients, their relatives, and ethnically matched unrelated controls; 247 probands and 249 controls were included in this study. In contrast to some studies, we found no evidence of significant differences either in the frequency of the genotypes 1-2 and 2-2 or allele 2 between the schizophrenic patients and the controls. A transmission disequilibrium test, run on the full set of 265 families yielded no evidence to support linkage disequilibrium. Linkage analysis with both parametric and non-parametric methods yielded strongly negative results. Our findings are consistent with other recent association studies which argue against the involvement of the 5-HT2a/T102C polymorphism in predisposition to schizophrenia. The positive findings reported to date might have occurred by chance or the apparent conflict may be due to genetic heterogeneity between samples.
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PMID:No association or linkage between the 5-HT2a/T102C polymorphism and schizophrenia in Irish families. 925 71

The T102C polymorphism at the 5-hydroxytryptamine 2a receptor (5HTR2a) gene was studied in 101 Chinese male schizophrenics and 103 controls. Genotyping revealed a predominance of allele 1 among schizophrenics. This is in contrast to previous reports in Caucasians and Japanese which showed an association of allele 2 of this polymorphism with schizophrenia.
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PMID:Association between allele 1 of T102C polymorphism, 5-hydroxytryptamine 2a receptor gene and schizophrenia in Chinese males in Singapore. 935 20

Activation of the inflammatory response system has been related to the pathophysiology of schizophrenia by several recent studies. Schizophrenic patients have varied levels of proinflammatory cytokines, such as interleukin (IL)-1, -6, and tumor necrosis factor (TNF)alpha in their peripheral blood or cerebrospinal fluid. These cytokines can modify the metabolism of neurotransmitters, influence neural development, and IL-1 has been implicated in acute, and, on the other hand, chronic neurodegeneration. They could therefore be of primary pathogenic importance, either in the acute disease or during those stages of brain development which possibly influence the sensitivity of a person to schizophrenia in later life. The cytokine regulation of brain development and its possible neuroimmune involvement in the pathogenesis of schizophrenia has been raised. One indication of the pathogenic role of IL-1 in schizophrenia would be a demonstration of the difference between schizophrenic patients and healthy controls at the gene level. Therefore we analyzed the polymorphism of the IL-1 gene complex in 50 schizophrenic patients and in 400 healthy blood donors. The following allelisms were analyzed: IL-1beta gene: base exchange polymorphisms at the positions -511 (relative to the transcriptional start site); IL-1alpha gene: base exchange polymorphism at the position -889; IL-1 receptor antagonist (IL-1RA) gene: variable numbers of 86-base pair tandem repeats in intron 2. The frequencies of the IL-1beta (-511) allele 1, IL-1alpha (-889) allele 2, and IL-1RA allele 1 were somewhat, but not significantly, higher in the schizophrenic patients as compared to the controls. These alleles are known to be located on the same haplotype. The number of carriers of this haplotype was significantly higher in the schizophrenia patients (17/50 vs 81/400) than in the controls (P=0.026, chi2). The frequencies of this haplotype were 0.38 and 0.27, respectively (P=0.0266, chi2). The number of homozygotes of this haplotype was significantly higher in the schizophrenia patients (P=0.0006, chi2). These data suggest that the cytokine aberrations in schizophrenia are, at least partly, genetically determined.
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PMID:Polymorphisms of the interleukin-1 gene complex in schizophrenia. 1020 41

Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease have been identified. However, several genes with small effect have been reported, though inconsistently, to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C) only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typical neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also included. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psychiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients with genotype 1/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizophrenia characterized by poor long-term outcome and poor response to neuroleptics.
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PMID:T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability. 1021 56

Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the DRD3ser-gly genotype in the schizophrenia patients with TD. The difference between the schizophrenia patients with TD and the controls was highly significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for multiple testing, as was the difference between the combined group of schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002). Comparing the schizophrenia patients with and without TD, genotypes containing the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02). DRD3 genotype and age at first antipsychotic treatment contributed significantly to total score on the Abnormal Involuntary Movements Scale (AIMS). The contribution of DRD3 to the variance in AIMS total was 5.2% and the total proportion of the variance accounted for by these two variables together was 11.9%. These results support and extend the report by Steen et al (1997) of an association between DRD3 and TD in schizophrenia patients.
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PMID:Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. 1039 14


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