title: Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant.
abstract: 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 Jönsson et al. (2003) (n=233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson 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.
authors.affiliation: Neurogenetics Section, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Hwang
authors.forename: C
authors.initials: C
authors.lastname: Zai
authors.forename: A
authors.initials: A
authors.lastname: Tiwari
authors.forename: D J
authors.initials: DJ
authors.lastname: Müller
authors.forename: M J
authors.initials: MJ
authors.lastname: Arranz
authors.forename: A G
authors.initials: AG
authors.lastname: Morris
authors.forename: P J
authors.initials: PJ
authors.lastname: McKenna
authors.forename: J
authors.initials: J
authors.lastname: Munro
authors.forename: S G
authors.initials: SG
authors.lastname: Potkin
authors.forename: J A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: H Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D001741:Black or African American; D019943:Amino Acid Substitution; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use*; D005260:Female; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy*; D044465:White People
chemical_list: D014150:Antipsychotic Agents; D050637:Receptors, Dopamine D3; D003024:Clozapine