The D2 subtype of dopamine receptor has been widely implicated in the pathogenesis of schizophrenia. Early evidence supporting an association between the Cys311Ser polymorphism of the D2 receptor gene (DRD2) and schizophrenia was subsequently refuted and, eventually, dismissed. From all 24 published case-control studies, we calculated a pooled estimate of this association. The pooled odds ratio was 1.3 for the Cys allele, which was highly significant (P = 0.007). The odds ratio derived from each study was unrelated to the ethnicity or gender composition of the sample, or the age of the control group. There was no evidence of publication bias or excessive influence attributable to any given study. Although more familybased studies are needed to confirm this relation, our results provide strong evidence that DRD2 influences susceptibility to schizophrenia. Molecular Psychiatry (2003) 8, 911-915. doi:10.1038/sj.mp.4001321Keywords: meta-analysis; association; dopamine; D2 receptor; gene; schizophrenia Dopamine system dysfunction has been widely implicated in the pathogenesis of schizophrenia. The most effective known treatments for schizophrenia are those that principally antagonize the D2 subtype of dopamine receptor.1 In fact, the D2 receptorbinding efficacy of neuroleptics is highly correlated with their ability to ameliorate symptoms.2 Furthermore, D2 receptor-binding density is increased in the brains of schizophrenic patients.2 When a functional variant of the D2 receptor gene (DRD2) was discovered 3 and found to be associated with the disorder, 4 a role for DRD2 in the genesis of schizophrenia was postulated. This mutation, a C-to-G transversion in codon 311, results in the substitution of cysteine (Cys) for serine (Ser) in the protein and, consequently, alters the physiology and function of the receptor. For example, the Cys variant of the D2 receptor has approximately half of the affinity for dopamine as that exhibited by the wild-type receptor. In addition, signal transduction in cells expressing this variant is reduced by 44%, an effect that is not because of impaired G-protein coupling but which may be mediated by lower efficiency of the variant-containing protein in activating the a subunit of the associated G-protein heterotrimer. Although the early evidence for association noted by Arinami et al 4 was strong, 21 of 22 subsequent studies of this putative association with schizophrenia failed to detect a significant relation. Thus, the initial finding of association has come to be regarded as a type-I inferential error.6 Yet, it is uncertain if this failure to identify consistently an association has been because of the low power of individual studies to detect a small effect, etiological heterogeneity, or random error in the absence of a true effect. To derive a powerful estimate of the true association between the Cys311Ser DRD2 polymorphism and schizophrenia, we performed a meta-analysis of all 24 published case-control studies in which this relation was examined.
Materials and methods
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