title: Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1).
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Genetic association study based on mutation detection and case-control analysis.
  
  
  METHODS
  All subjects were unrelated and ascertained from general (secondary care) psychiatric inpatient and outpatient services.
  
  
  METHODS
  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.
  
  
  METHODS
  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<.001), composed of 1 risk haplotype (P =.01) and 2 protective haplotypes, 1 common (P =.006) and 1 rare (P<.001). Specific risk and protective haplotypes were replicated in the Dublin sample (P =.02,.047, and.006, respectively). The only phenotypic variable associated with any haplotype was between the common protective haplotype and higher educational achievement (P =.02, corrected for multiple tests).
  
  
  CONCLUSIONS
  DTNBP1 is a susceptibility gene for schizophrenia. Specific risk and protective haplotypes were identified and replicated. Association with educational achievement may suggest protection mediated by IQ, although this needs to be confirmed in an independent data set.
authors.affiliation: Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, Wales.
authors.forename: N M
authors.initials: NM
authors.lastname: Williams
authors.forename: A
authors.initials: A
authors.lastname: Preece
authors.forename: D W
authors.initials: DW
authors.lastname: Morris
authors.forename: G
authors.initials: G
authors.lastname: Spurlock
authors.forename: N J
authors.initials: NJ
authors.lastname: Bray
authors.forename: M
authors.initials: M
authors.lastname: Stephens
authors.forename: N
authors.initials: N
authors.lastname: Norton
authors.forename: H
authors.initials: H
authors.lastname: Williams
authors.forename: M
authors.initials: M
authors.lastname: Clement
authors.forename: S
authors.initials: S
authors.lastname: Dwyer
authors.forename: C
authors.initials: C
authors.lastname: Curran
authors.forename: J
authors.initials: J
authors.lastname: Wilkinson
authors.forename: V
authors.initials: V
authors.lastname: Moskvina
authors.forename: J L
authors.initials: JL
authors.lastname: Waddington
authors.forename: M
authors.initials: M
authors.lastname: Gill
authors.forename: A P
authors.initials: AP
authors.lastname: Corvin
authors.forename: S
authors.initials: S
authors.lastname: Zammit
authors.forename: G
authors.initials: G
authors.lastname: Kirov
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000235:genetics* / Q000494:pharmacology; D016022:Case-Control Studies; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004522:Educational Status; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007360:Intelligence / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins