Association between schizophrenia and homozygosity at the dopamine D3 receptor gene (original) (raw)
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No association between schizophrenia and homozygosity at the D3 dopamine receptor gene
American Journal of Medical Genetics, 1993
The D3 dopamine receptor gene is an important candidate gene for schizophrenia, since (because of its almost exclusive expression in the limbic system) it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. A BalI restriction fragment length polymorphism of the D3 dopamine receptor gene has been typed in 107 schizophrenic patients and 98 normal controls from Sichuan (China). With regard to alleles or genotypes, no significant differences were obtained between controls from Europe and China, between patients and controls, and between patient subgroups and controls. These results indicate a lack of association between schizophrenia and the D3 dopamine receptor gene in our sample. Our findings are at variance with reports of a significant excess of homozygosity at the D3 dopamine receptor gene in schizophrenic patients from Wales (United Kingdom) and Alsace (France). In conclusion, further studies will be needed with larger samples of patients from Wales and Alsace as well as with samples of different racial groups to prove or disprove the initial positive association between schizophrenia and genotypes of the D3 dopamine receptor gene. © 1993 Wiley-Liss, Inc.
Lack of association between schizophrenia and alleles in the dopamine D 3 receptor gene
Acta Psychiatrica Scandinavica, 1993
Dopamine receptor dysfunction has been implicated in the pathophysiology of schizophrenia. Schizophrenic patients (n = 76) and control subjects (n = 53) were examined for allele frequencies in a 2-allele BalI polymorphism, causing a serine-->glycine amino acid substitution in the coding sequence of the dopamine D3 receptor gene. No statistical significant differences of allele frequencies or genotype frequencies could be found between the two groups. Neither were there any significant relationships between allele frequencies and a number of clinical variables within the schizophrenic subsample. However, if not corrected for multiple testing, an association was found between homozygosity and positive response to neuroleptic drugs. The present study does not provide evidence that the BalI polymorphism in the dopamine D3 receptor gene is involved in the pathophysiology of schizophrenia. Further investigations with an increased number and variety of patients concerning response to neuroleptic drugs and expression of the receptor in human brain should be performed to definitively exclude this hypothesis.
American Journal of Medical Genetics, 1993
Using a case-control design, a reported association of schizophrenia with homozygosity at the dopamine D3 receptor gene locus was investigated in a group of patients (n = 53), with schizophrenia (DSM-III-R), and psychiatrically normal controls (n = 61), matched for ethnicity and area of residence. No significant differences in the distribution of alleles or genotypes between the two groups could be deteched. However, among patients with a family history of schizophrenia, as compared to controls without such family history, an association with allele 1 at this locus was noted (Odds ratio 12.4, C.I. 1.61, 96.35). © 1993 Wiley-Liss, Inc.
Further evidence of no linkage between schizophrenia and the dopamine D3 receptor gene locus
American Journal of Medical Genetics, 1994
The dopamine hypothesis of schizophrenia proposed that dopaminergic pathways are involved in the etiology of the disease. In particular, interest among psychiatrists has focused on the D, receptor because of its affinity to antipsychotic drugs. Recently a new dopamine receptor gene has been cloned, and named the dopamine D, receptor. The D3 receptor is a potential site for antipsychotic drug action and may be involved in the pathophysiology of schizophrenia. We have carried out a linkage study between the susceptibility gene for schizophrenia and polymorphism of the dopamine D3 receptor gene in two Japanese pedigrees. The LOD scores were negative for all genetic models and for all affective status at a recombination fraction 8 = 0. Linkage of DRD, has been excluded for the model 1 (dominant model) and the model 3 (recessive model). The LOD score was-3.43 at 8 = 0 for model 1 (dominant model) and broad definition of affected status. These results were consistent with previous studies.
There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, À205-G/A, À7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder (N=118) and controls (N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the À205-A/G polymorphisms and disease, an excess of allele À7685-C was observed in patients ( p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium ( pb0.0001) and strongly associated with disease ( pb1Â10 À5 ). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required. D
Homozygosity at the dopamine D3 receptor gene in schizophrenic patients
Neuroscience Letters, 1996
Dopamine receptors have long been implicated in the etiology of schizophrenia. It has been reported an association of schizophrenia with homozygosity at the dopamine D3 receptor gene locus. We have investigated the distribution of a D3 receptor gene polymorphism (Bali) in 107 schizophrenic Spanish patients and 100 healthy matched controls. No statistically significant differences between the patients and control group were detected with respect to either allele frequencies or genotype distribution. However, if not corrected for multiple testing, a correlation was found between homozygosity and early age of onset of schizophrenia (X 2 = 3.1, df = 1, P = 0.03) and between A1 allele frequency and disorganized and undifferentiated schizophrenia (X 2= 3.4, df = 1, P = 0.03; X2= 2.7, df = 1, P = 0.05, respectively). These results suggest the possibility that D3 polymorphisms may be among the physiological factors underlying schizophrenia; though not the determining factor.
American Journal of Medical Genetics, 1997
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.
Neuroscience Letters, 2000
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.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2007
This study aims to further evaluate the controversial association between the Ser9Gly polymorphism in codon 9 of the D3 dopamine receptor gene (DRD3) and schizophrenia in psychiatric inpatients acutely hospitalized in two general hospitals in Madrid, Spain. The Ser9Gly polymorphism of the DRD3 was examined in 178 schizophrenic patients, 286 patients with other psychiatric diagnoses, and 132 controls recruited. Genotype frequencies were in Hardy‐Weinberg equilibrium. No association was found between schizophrenia and the Ser9Gly polymorphism of the D3 dopamine receptor gene. © 2006 Wiley‐Liss, Inc.
Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia
2006
The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5 nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P = 0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis.