THE DOPAMINE D-3 RECEPTOR (DRD3) SER(9)GLY POLYMORPHISM AND SCHIZOPHRENIA - A HAPLOTYPE RELATIVE RISK STUDY AND ASSOCIATION WITH CLOZAPINE RESPONSE

Several lines of evidence suggest that the dopamine D-3 receptor is in volved in the pathophysiology of schizophrenia.(1-3) The D-3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine subs titution in the N-terminus of the receptor.(4) Shaikh and colleagues(5 ) have reported a significant association between the DRD3 Ser, allele and the Ser(9)/Ser(9) genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser(9) and the Ser(9)/Ser(9) g enotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports(6,7) of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser(9)/Ser(9) genotype was more freq uent in patients who did not respond to clozapine, These data represen t the most comprehensive examination of DRD3 Ser(9)Gly in schizophreni a to date, We have therefore determined DRD3 Ser(9)Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have g enotyped 68 schizophrenics participating in double-blind clozapine tri als, We do not find that Ser(9) is preferentially transmitted in schiz ophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, an d do not replicate the association between DRD3 and clozapine response . These data suggest that allelic variation in DRD3 may not play a rol e in the pathophysiology of schizophrenia or in clozapine response.