The dopamine D₃ receptor (DRD3) Ser₉Gly polymorphism and schizophrenia: A haplotype relative risk study and association with clozapine response

Several lines of evidence suggest that the dopamine D₃ receptor is involved in the pathophysiology of schizophrenia. The D₃ receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser₉ allele and the Ser₉/Ser genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser₉ and the Ser₉/Ser₉ genotype were found to be significantly associated with schizophrenia, investigators could not confirm excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser₉/Ser₉ genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser₉Gly in schizophrenia to date. We have therefore determined DRD3 Ser₉Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser₉ is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.