Identification in 2 Independent Samples of a Novel Schizophrenia Risk Haplotype of the Dystrobrevin Binding Protein Gene (DTNBP1)

Abstract

Context: Recent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia. Thus far, no specific risk haplotype has been identified in more than 1 study. Objectives: To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype. Design: Genetic association study based on mutation detection and case-control analysis. Setting: All subjects were unrelated and ascertained from general (secondary care) psychiatric inpatient and outpatient services. Participants: The Cardiff, Wales, sample included 708 white subjects from the United Kingdom and Ireland (221 females) who met DSM-IV criteria for schizophrenia and were individually matched for age, sex, and ethnicity to 711 blood donor controls (233 females). Mean ± SD age at first psychiatric contact for cases was 23.6 ± 7.7 years; mean age at ascertainment was 41.8 ± 13.5 years. The Dublin, Ireland, sample included 219 white subjects from the Republic of Ireland who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and 231 controls. The mean age of the Irish cases was 46.0 ± 8.5 years; mean age at first psychiatric contact was 25.2 ± 12.4 years. Main Outcome Measure: Evidence for association between the DTNBP1 locus and schizophrenia. Results: In the Cardiff sample, there was no evidence for association with previously implicated haplotypes but strong evidence for association with multiple novel haplotypes. Maximum evidence was found for a novel 3-marker haplotype (global P