Schizophrenia is not associated with DRD4 48-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.