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 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

A putative association of schizophrenia with a Msc I restriction fragment length polymorphism at the dopamine D3 receptor gene locus (DRD3) was tested among Indian families, using haplotype relative risk analysis and the transmission disequilibrium test (n=66 families and 58 sets of transmissions, respectively). A significant association either with homozygosity or with allele 1 at the biallelic polymporphism could not be detected.
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PMID:Association study of schizophrenia among Indian families. 1040 93

There is considerable controversy regarding a putative association between schizophrenia and a biallelic BalI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3), although meta-analyses of published data suggest an association. If such an association exists, it may be detectable at markers physically close to DRD3. Accordingly, we conducted a case-control association study using D3S1310, a short tandem repeat polymorphism located approximately 700 kb telomeric to DRD3 on chromosome 3q13.3. The subjects were Swedish patients with schizophrenia (DSM III-R criteria, n = 110) and screened adult controls (n = 83). A trend for a negative association with the 141 bp allele was detected (chi2 = 7.6, d.f. = 1, P = 0.006; odds ratio 0.46, 95% confidence intervals 0.26, 0.81). However, following corrections for multiple comparisons using subgroups (n = 15) the difference was not significant. Also, due to the risk for population stratification in case-control association studies the results must be treated as tentative. If replicated the results may lend further support for the proposition of an association between schizophrenia and DRD3 or a gene in close proximity to DRD3 on chromosome 3q.
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PMID:Trend for an association between schizophrenia and D3S1310, a marker in proximity to the dopamine D3 receptor gene. 1040 2

Dopamine D3 receptor gene (DRD3) variants have been implicated in the pathogenesis of psychiatric disorders. Many studies, however, have failed to replicate the association of DRD3 with schizophrenia. A possible reason for this may lie in the definition of phenotype, which is traditionally based on psychiatric diagnosis. In this study we investigated the possibility that variants of the DRD3 gene might be associated with symptomatology in a sample of subjects affected by major psychoses. Two hundred and eleven inpatients affected by major psychoses were assessed by the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and were also typed for the DRD3 variants using polymerase chain reaction techniques. Mania, depression, delusion, and disorganization were the four symptomatologic factors used as phenotype definitions. DRD3 variants were not associated with these symptomatologic factors, and consideration of possible stratification effects, such as sex and psychiatric diagnosis, did not reveal any association either.
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PMID:Dopamine D3 receptor gene not associated with symptomatology of major psychoses. 1049 Jul 2

The association between schizophrenia and the Ser9Gly variant of the dopamine D3 receptor gene (DRD3) has been the subject of numerous studies. Under meta-analysis this site, or one or more in linkage disequilibrium with it, appears to contribute a small increase to the relative risk of schizophrenia. In this study, 768 bp of the 5'-leader region of DRD3 mRNA was screened for polymorphisms to assess their contribution to the association of DRD3 with schizophrenia. A cluster of three single nucleotide polymorphisms (SNPs) was identified in tight linkage disequilibrium with each other and with the Ser9Gly polymorphism. One of the 5'-leader SNPs encodes a Lys9Glu variant within a 36 amino acid residue stretch of an upstream open reading frame (uORF). Two common haplotypes are found in the population examined; one is linked to the Ser9 coding variant and the other to the Gly9 variant. A panel of 73 schizophrenic patients and 56 matched controls recruited from the East Anglia region of the United Kingdom was screened for disease association at these sites. Since the 5'-leader and coding sites are in tight disequilibrium, the combined genotype of all 4 sites was scored for each patient. A significant association was seen between disease and the frequency distribution of these genotypes (chi2 = 13.19, d.f. = 3, P = 0.0042; Cochran method for sparse cells applied). A 20% excess of one of the heterozygous genotypes, in which the sequences differ at three of the four SNPs, including Ser9/Gly9 in the receptor and Lys9/Glu9 in the uORF, was found in the patient group. An absence of association of disease with the Ser9Gly polymorphism had previously been reported for this panel. This suggests that these SNPs and the corresponding coding changes may exert a combined or synergistic effect on susceptibility to schizophrenia.
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PMID:A cluster of single nucleotide polymorphisms in the 5'-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. 1067 Jul 76

Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.
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PMID:Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder. 1069 26

A 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.
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PMID:The genes for major psychosis: aberrant sequence or regulation? 1086 81

Although the association between the Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia has been investigated by many research groups, it is not known whether the Ser9Gly polymorphism alone or a variation in linkage disequilibrium may effect susceptibility to schizophrenia. We searched the 5' region of the DRD3 gene and found three novel polymorphisms: -712G/C, -205A/G, and Ala38Thr. The Ala38Thr polymorphism is located in the first transmembrane region and is conserved in the monkey, mouse, and rat. Case-control comparisons in 153 Japanese schizophrenia patients and 122 Japanese controls did not suggest an association between Ala38Thr and schizophrenia. However, there was a marginally significant association between the Ser9 allele of the Ser9Gly polymorphisms and schizophrenia (P = 0.02). Furthermore, there was a highly significant association between haplotypes of the -712G/C, -205A/G, and Ser9Gly polymorphisms and schizophrenia (P = 0.0007, corrected P = 0.007). These positive findings were replicated in an additional 99 Japanese schizophrenia patients and 132 controls (P = 0.04 and 0.0004, respectively). The most allelic differences of the Ser9Gly polymorphism between patient and control groups arose from the chromosome carrying specific alleles of the other three polymorphisms. This study indicates unknown variant(s) in linkage disequilibrium with the DRD3 haplotypes associated with schizophrenia.
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PMID:Mutation and association analysis of the 5' region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia. 1088 55

Schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities or physical anomalies supports a neurodevelopmental etiology, especially in early onset schizophrenia. Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse. In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression. In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166-174 bp) between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172-176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 Ball gene polymorphism in the same population. These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia.
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PMID:Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. 1103 92

Alterations in dopamine neurotransmission have been hypothesized to play a role in the etiology of schizophrenia. We considered the dopamine D3 receptor gene on chromosome 3 as a candidate gene for an association analysis. We compared PCR-based genotype markers for healthy controls (n=120) and patients (n=95) with schizophrenia and schizophrenia spectrum disorders as diagnosed by consensus according to DSM-III-R. Our results possibly indicate an association of schizoaffective disorder with DRD3 homozygosity (P=0.056).
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PMID:Association study of schizophrenia spectrum disorders and dopamine D3 receptor gene: is schizoaffective disorder special? 1106 91


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