title: Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes.
abstract: In a previous study we identified a relatively homogeneous subtype of schizophrenia characterized by pervasive cognitive deficit, which was the exclusive contributor to our findings of linkage to 6p25-p24. The 6p region contains Dysbindin (DTNBP1), considered to be one of the major schizophrenia candidate genes. While multiple studies have reported association between genetic variation in DTNBP1 and schizophrenia, the findings have been inconsistent and controversial, leading to recent calls for systematic re-examination and unambiguous evidence of association. To address this, we have undertaken a comprehensive survey of common genetic variation within DTNBP1 and its association with schizophrenia, using a HapMap-based gene-tagging approach. We genotyped 39 tSNPs in a sample of 336 cases and 172 controls of Anglo-Irish ancestry, with the phenotype defined as clinical schizophrenia, and as composite neurocognitive endophenotypes. Allele and haplotype frequencies, and LD structure in our control sample were similar to those in other European populations. Using multivariate generalized linear modeling, we observed no significant association between any tSNP and any outcome variable. Association with haplotypes was examined across the gene and in the previously associated 5' region. Neither global haplotype tests, nor specific analysis of the "risk" haplotype previously reported in an ethnically related population, the Irish high-density schizophrenia families, showed significant evidence of association with schizophrenia or with the neurocognitive endophenotypes in our sample. The framework and results of this study should facilitate further attempts at re-analysis of DTNBP1, in terms of standardized approaches to both phenotype definition and analysis of genetic variation.
authors.affiliation: Laboratory for Molecular Genetics, Western Australian Institute for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Peters
authors.forename: Steven
authors.initials: S
authors.lastname: Wiltshire
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Milan
authors.initials: M
authors.lastname: Dragović
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Badcock
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.forename: Sarah
authors.initials: S
authors.lastname: Howell
authors.forename: Chris
authors.initials: C
authors.lastname: Ellis
authors.forename: Sonja
authors.initials: S
authors.lastname: Bouwer
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Lyle J
authors.initials: LJ
authors.lastname: Palmer
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
authors.forename: Assen
authors.initials: A
authors.lastname: Jablensky
mesh_terms: D001315:Australia / Q000453:epidemiology; D002352:Carrier Proteins / Q000235:genetics*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004739:England / Q000208:ethnology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007494:Ireland / Q000208:ethnology; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins