A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia [published erratum appears in Mol Psychiatry 1998 Sept;3:458]

University of Milan, Milano, Lombardy, Italy
Molecular Psychiatry (Impact Factor: 14.5). 04/1998; 3(2):141-9. DOI: 10.1038/
Source: PubMed


We performed a meta-analysis of over 30 case-control studies of association between schizophrenia and a bi-allelic, Bali polymorphism in exon 1 of the dopamine D3 receptor gene. We observed a significant excess of both forms of homozygote in patients (P = 0.0009, odds ratio (OR) = 1.21, 95% Confidence Interval (CI) = 1.07-1.35) in the combined sample of 5351 individuals. No significant heterogeneity was detected between samples and the effects did not appear to be the product of publishing bias. In addition we undertook an independent, family-based association study of this polymorphism in 57 parent/proband trios, taken from unrelated European multiplex families segregating schizophrenia. A transmission disequilibrium test (TDT) showed a significant excess of homozygotes in schizophrenic patients (P = 0.004, odds ratio (OR) = 2.7, 95% CI = 1.35-5.86). Although no significant allelic association was observed, a significant association was detected with the 1-1 genotype alone (P = 0.02, OR = 2.32, 95% CI = 1.13-4.99). In addition when the results of the family-based association study were included in the meta-analysis, the homozygosity effect increased in significance (P = 0.0002, OR = 1.23, 95% CI = 1.09-1.38). The results of the meta-analysis and family-based association study provide independent support for a relationship between schizophrenia and homozygosity at the Bali polymorphism of the D3 receptor gene, or between a locus in linkage disequilibrium with it.

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    • "Therefore, DRD3 is considered a promising functional and positional candidate gene for SZ. One of the most extensively investigated polymorphisms within this gene is the single nucleotide polymorphism (SNP) rs6280 (Ser9Gly) in exon 2, resulting in a serine (Ser) to glycine (Gly) substitution at codon 9. Some studies suggested an association of the Ser allele [Ishiguro et al., 2000], the Gly allele [Kennedy et al., 1995], or homozygotes of both types [Crocq et al., 1992; Williams et al., 1998] with SZ. However, other studies failed to detect a positive association for this marker, in agreement with two recent Grant sponsor: National Natural Science Foundation of China; Grant numbers: 30570430, 81000583, 81000578; Grant sponsor: Tsinghua Yu- Yuan Medical Sciences Fund; Grant number: 20240000518. "
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    ABSTRACT: The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine-to-serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over-represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E-5). The derived C-allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene.
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    • "All five have an extracellular amino terminus, seven transmembrane domains and an intracellular carboxyl terminus. Abnormalities in dopamine neurotransmission are implicated in the aetiology of neurological and psychiatric disorders including schizophrenia (Williams et al. 1998) and Parkinson's disease (Oliveri et al. 2000). "
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