European multicentre association study of schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms

Abstract

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.

Functional polymorphisms in dopamine and serotonin pathway genes

“…The Ser9 variant is referred to as allele 1, and the Gly9 variant is referred to as allele 2. Significant associations (Po0.002) between the 1-1 genotype and schizophrenia have been reported in case-control studies in French and English populations [Crocq et al, 1992;Mant et al, 1994;Asherson et al, 1996;Spurlock et al, 1998a]. The results of a meta-analysis of case-control studies were also in agreement with those previous findings (P 5 0.004) ].…”

Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a Portuguese population

“…Our findings for TaqI-A and Ser311Cys polymorphisms do not corroborate previous findings obtained with case-control association studies (Arinami et al, 1994(Arinami et al, , 1996 and meta-analysis (Jonsson et al, 2003a). However, they are in agreement with case-control association studies carried out in different populations (Itokawa et al, 1993;Sasaki et al, 1996;Tanaka et al, 1996;Spurlock et al, 1998;Hori et al, 2001;Himei et al, 2002). Other authors also have obtained inconsistent results with association studies with the y141C InsyDel polymorphism at the DRD2 gene (Li et al, 1998;Breen et al, 1999;Jonsson et al, 1999;Himei et al, 2002).…”

“…Several case-control studies have investigated the possible involvement of the DRD2 and DRD3 genes in schizophrenia, but the results are inconclusive (Dubertret et al, 1998;Spurlock et al, 1998;Williams et al, 1998;Kremer et al, 2000;Hori et al, 2001;Himei et al, 2002;Morimoto et al, 2002). However, meta-analyses have recently supported the involvement of the DRD2 and DRD3 genes in the pathogenesis of schizophrenia (Jonsson et al, 2003a,b).…”

A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia

“…The inverted funnel shape of the plot indicates an absence of publication bias, as it shows no evidence of a failure to publish small studies with low odds ratios. 26 Crocq et al, 25 1.7 1.19-2.44 Asherson et al, 42 Spurlock et al 43 Control Table 2 As the study involved pooling data from a number of European Centres, a heterogeneity analysis was applied. Table 3 shows the distribution of parental alleles transmitted and not transmitted to patients, in each European Centre.…”