Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant

D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jonsson et al. (2003) (n = 233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jonsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n = 758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies. The Pharmacogenomics Journal (2010) 10, 200-218; doi:10.1038/tpj.2009.65; published online 22 December 2009