title: Dysbindin (DTNBP1) and the biogenesis of lysosome-related organelles complex 1 (BLOC-1): main and epistatic gene effects are potential contributors to schizophrenia susceptibility.
abstract: BACKGROUND
  The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching.
  
  
  METHODS
  A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results.
  
  
  RESULTS
  We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing.
  
  
  CONCLUSIONS
  Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.
authors.affiliation: Neuropsychiatric Genetics Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College, Dublin, Ireland. morrisdw@tcd.ie/acorvin@tcd.ie
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
authors.forename: Kevin
authors.initials: K
authors.lastname: Murphy
authors.forename: Niamh
authors.initials: N
authors.lastname: Kenny
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.forename: Kevin A
authors.initials: KA
authors.lastname: McGhee
authors.forename: Siobhan
authors.initials: S
authors.lastname: Schwaiger
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Nangle
authors.forename: Gary
authors.initials: G
authors.lastname: Donohoe
authors.forename: Sarah
authors.initials: S
authors.lastname: Clarke
authors.forename: Paul
authors.initials: P
authors.lastname: Scully
authors.forename: John
authors.initials: J
authors.lastname: Quinn
authors.forename: David
authors.initials: D
authors.lastname: Meagher
authors.forename: Patrizia
authors.initials: P
authors.lastname: Baldwin
authors.forename: Niall
authors.initials: N
authors.lastname: Crumlish
authors.forename: Eadbhard
authors.initials: E
authors.lastname: O'Callaghan
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Aiden P
authors.initials: AP
authors.lastname: Corvin
mesh_terms: D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D004198:Disease Susceptibility; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D001678:Organelle Biogenesis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C104378:BLOC1S1 protein, human; D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins