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)

Dopamine D3 receptor (DRD3) was demonstrated to have important implications in schizophrenia, because it binds antipsychotic drugs and is abundant in the limbic system of the brain. Several groups attempted to find an association between a serine-to-glycine polymorphism at codon 9 of the DRD3 gene (Ser9Gly) and schizophrenia; however, the results were inconsistent. We conducted a case-control association study in Han Chinese schizophrenic patients from Taiwan, to examine the relationship of this serine-to-glycine polymorphism and schizophrenia. We noted no significant differences of genotype distribution, allele frequencies, or homozygosity proportion of this polymorphism between schizophrenic patients (N = 178) and controls (N = 100). When patients were divided according to sex, or presence or absence of family history, the differences were still not significant. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia.
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PMID:Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia. 903 4

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

This study follows the observation of an association between homozygosity of an Mscl polymorphism in exon 1 and schizophrenia, which gives rise to a glycine to serine substitution and may alter the functional properties of the receptor. Alternatively the polymorphism may not itself be of functional significance but may be in linkage disequilibrium with another genetic variant in the coding or regulatory regions. To examine the second possibility we have screened all six exons of DRD3 by single-stranded conformational polymorphism analysis (SSCP) in 36 cases and 36 controls. Our findings suggest that the gene is highly conserved since we found no other mutations which alter protein structure. However we did detect a 5-bp deletion in the 3' intronic sequence flanking exon 5 which occurred in 7-8% of subjects within both case and control samples. A single bp substitution (g to a) in exon 3, which does not alter an amino acid was found in one affected individual. In addition we carried out a linkage study of 24 families multiply affected with schizophrenia and a non-parametric linkage study of 90 affected sibling pairs. These studies give no support for either major or moderate gene effects on schizophrenia susceptibility. Finally we have extended our association sample and observe a non-significant excess of homozygotes for the Mscl polymorphism in the sample overall (chi 2 = 2.09, 1 d.f., P = 0.15). The excess of homozygotes is specific to males (chi 2 = 4.617, 1 d.f., P = 0.032) and not females (chi 2 = 0.243, 1 d.f., NS). When these data are added to our previous published data a highly significant excess of homozygotes is observed in males (chi 2 = 13.766, 1 d.f., P = 0.00021) but not females (chi 2 = 0.606, 1 d.f., NS). In conclusion the accumulated data suggest strongly that genetic variation at the DRD3 locus increases susceptibility of schizophrenia, at least in males. At present the Mscl polymorphism in exon 1 of the gene remains a candidate for bringing about functional change in the receptor but this has not been formally tested. Other coding region polymorphisms have not been detected but it remains possible that variation within the promoter may alter receptor function.
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PMID:Linkage, association and mutational analysis of the dopamine D3 receptor gene in schizophrenia. 911 22

Several lines of evidence suggest that the dopamine D3 receptor is involved in the pathophysiology of schizophrenia. The D3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser9 allele and the Ser9/Ser9 genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser9 and the Ser9/Ser9 genotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser9/Ser9 genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser9Gly in schizophrenia to date. We have therefore determined DRD3 Ser9Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser9 is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.
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PMID:The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. 949 16

As part of the European Multicentre Association Study of Schizophrenia (EMASS), we studied polymorphisms in the dopamine DRD2 and DRD3 receptor genes. The EMASS collaboration was established to create a large, statistically powerful sample of schizophrenic patients and controls from different European centres. Previous studies have suggested associations between schizophrenia and the Ser311Cys polymorphism in exon 7 of the dopamine DRD2 receptor gene [Arinami et al., (1994): Lancet 343:703-704] and a polymorphism Ser9gly in exon 1 of the dopamine DRD3 receptor gene [Crocq et al. (1992): J Med Genet 29:858-860]. We tested for these associations in samples of 373 and 413, and 311 and 306 patients and controls, respectively. We found no evidence for allelic association between schizophrenia and the Cys311 variant of the DRD2 receptor gene and no homozygotes for this variant were observed by any group. However, an excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi2 = 8.54, P = 0.003, odds ratio = 1.64, 95% CI = 1.18-2.29). We also observed a significant excess of the 1-1 (Ser9Ser) genotype (chi2 = 8.13, P = 0.004, odds ratio = 1.7, 95% CI = 1.18-2.4). No evidence of heterogeneity between samples was detected and there was no evidence of an allelic association. These findings suggest that the rare Cys311 variant in exon 7 of the DRD2 receptor gene does not play a role in the pathogenesis of schizophrenia in European populations. Currently, our results do support the previous findings of an association between increased homozygosity of the Ser/Gly variant of the Dopamine D3 receptor gene and schizophrenia.
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PMID:European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms. 951 83

The dopamine D3 (DRD3) receptor gene has been implicated in the aetiology of schizophrenia as a candidate gene since it combines both the dopamine receptor and limbic hypotheses of the disease. Previous association studies of a DRD3/MscI polymorphism suggested an increased frequency of homozygosity at the DRD3 receptor gene in schizophrenia. Homozygosity appeared to be particularly frequent in male patients, individuals with family history of the disease and in good responders to neuroleptic treatment. Many studies have since examined this polymorphism and have altered or extended the original homozygosity hypothesis. In this study, we have investigated the distribution of the DRD3/MscI polymorphism in 198 Irish schizophrenic patients and 235 ethnically matched controls. Patients and controls showed-similar allele and genotype frequencies. Furthermore, linkage analysis using two microsatellite markers flanking the DRD3 gene was performed on 265 Irish schizophrenic families, with substantially negative results. Our findings, in combination with a review of previous studies do not support a role for the DRD3/MscI polymorphism in the pathogenesis of schizophrenia.
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PMID:Examination of new and reported data of the DRD3/MscI polymorphism: no support for the proposed association with schizophrenia. 957 39

The involvement of dopamine in the etiology of schizophrenia is suggested by a number of neurobiological and pharmacological data, the dopamine D3 receptor (DRD3) being selectively expressed in brain regions which may be specifically involved in the risk for schizophrenia. The gene coding for DRD3 has thus been extensively analyzed. Since the initial report providing substantial evidence for an association of homozygosity of either allele of the gene coding for DRD3 (BalI polymorphisms) with schizophrenia, a flurry of replicating studies has appeared, which have been split into confirmations and nonreplications in North European Caucasian, Mediterranean, Asian, American, and African populations. The involvement of DRD3 polymorphisms thus remains questionable, particularly as no linkage studies have favored a nonrandom segregation of DRD3 alleles and schizophrenia. We performed a metaanalysis from 29 independent samples, from 24 different association studies so far published, allowing the examination of 2,619 schizophrenic patients and 2,517 controls. No significant differences of genotype counts were noted between patients and controls for the whole sample, considering frequency of any genotype. Starting from the high variability of the genotypes in different geographical areas, the impact of ethnic heterogeneity was taken into account. When the studies were reorganized in five groups according to geographical origin of samples, both homozygosity and 1-1 genotype revealed significant heterogeneity (P < 0.05). We specifically found an excess of homozygosity and 1-1 genotype in schizophrenic patients only in the African and Caucasian groups (P < 0.05). The present analysis suggests a small but significant effect of DRD3 in the susceptibility to schizophrenia, at least in Caucasians.
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PMID:Meta-analysis of DRD3 gene and schizophrenia: ethnic heterogeneity and significant association in Caucasians. 967 78

The D3-dopamine receptor gene, DRD3, has been considered as a candidate gene in several disorders in which the dopaminergic system has been implicated including Tourette syndrome and schizophrenia. The DRD3 studies to date have all used as the gene marker a Bal I polymerase chain reaction restriction fragment length polymorphism (PCR RFLP). There have been recent reports on a second marker, an Msp I PCR RFLP, that lies 40 kb downstream. We have typed a sample of 16 Tourette syndrome families with both markers and observed significant linkage disequilibrium between the two markers but no apparent association of either marker with Tourette syndrome.
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PMID:The Bal I and Msp I polymorphisms in the dopamine D3 receptor gene display, linkage disequilibrium with each other but no association with Tourette syndrome. 968 22

In an association study of the Bal I polymorphism in the dopamine D3 receptor (DRD3) gene in a French Caucasian population, global comparison of patients with schizophrenia (n = 89, DSM-III-R criteria) and controls (n = 52) led to non-significant differences. However, the homozygosity was significantly more frequent in schizophrenic patients with lifetime substance abuse comorbidity (n = 36) as compared to patients with no history of substance abuse (P = 0.010) or to controls (P = 0.047) and in neuroleptic responder patients as compared to treatment-refractory patients (n = 19; P = 0.037). The combined characteristics treatment response and lifetime substance abuse were strongly associated with homozygosity. We propose that homozygosity for the Bal I polymorphism DRD3 gene is associated with predisposition to substance abuse and/or the pharmacosensitive characteristic of schizophrenia rather than with schizophrenia itself, an hypothesis in agreement with the positive association of this polymorphism with opiate dependence (see companion article by Duaux et al) and the involvement of DRD3 in both pharmacodependence mechanisms and antipsychotic effects of neuroleptics.
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PMID:Dopamine D3 receptor gene variants and substance abuse in schizophrenia. 970 43

We determined allele frequencies for polymorphisms at several loci of interest in neuropsychiatry-tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), ciliary neurotrophic factor (CNTF), and the mu opioid receptor (OPRM1)-in samples of individuals from populations in several different parts of the world. Associations with psychiatric illness have been proposed for specific polymorphisms at TPH (suicide-related behaviors and impulsivity), DRD3 (schizophrenia and bipolar affective disorder), SLC6A3 (susceptibility to cocaine-induced paranoia and attention-deficit disorder), CNTF (psychosis), and OPRM1 (substance dependence). APOE alleles are related to risk of Alzheimer disease. We found significant allele frequency variation among populations at all six loci. These results will provide a global framework of normal variation at these loci that might have functional significance or otherwise be related to susceptibility to various disorders or behavioral phenomena. Knowledge of this variation can be important for study design and data interpretation when individuals from various population groups are research subjects and may eventually help lead to a better understanding of behavioral adaptation.
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PMID:Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), mu opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF)). 979 Jul 47


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