Schizophrenia is not associated with DRD448-base-pair-repeat length or individual alleles: results of a meta-analysis

Background The gene DRD4, coding for dopamine receptor D4, was considered a candidate for association with schizophrenia based on its upregulation in postmortem schizophrenic brain and affinity for clozapine. Many studies sought allelic association of a 48-base-pair repeat in DRD4 exon 3 with schizophrenia, but found no strong evidence for a relationship. The present work sought to determine if this observation reflected the true absence of association or the low power of individual studies. Methods We performed four meta-analyses, sequentially considering the two-, four-, and seven-repeat alleles as risk alleles, and then considering repeat length of the 48-base-pair segment as a risk factor. Each meta-analysis included at least 2300 cases and 2100 controls from 14–16 studies. Results The pooled odds ratio from each analysis approximated 1.0, and none were significant. Heterogeneity was not observed, although gender moderated the effects of repeat length and the seven-repeat allele. Conclusions Despite over 90% power to detect a significant odds ratio of 1.4 or less, none was observed. This polymorphism seems not to influence risk for most schizophrenia cases; however, a sex-dependent relationship, or a role in some clinical features of the disorder, cannot be excluded and should be pursued experimentally.