title: Sequence variation in DOCK9 and heterogeneity in bipolar disorder.
abstract: BACKGROUND
  Linkage of bipolar disorder to a broad region on chromosome 13q has been supported in several studies including a meta-analysis on genome scans. Subsequent reports have shown that variations in the DAOA (G72) locus on 13q33 display association with bipolar disorder but these may not account for all of the linkage evidence in the region.
  
  
  OBJECTIVE
  To identify additional susceptibility loci on 13q32-q33 by linkage disequilibrium mapping and explore the impact of phenotypic heterogeneity on association.
  
  
  METHODS
  In the initial phase, 98 single nucleotide polymorphism (SNPs) located on 13q32-q33 were genotyped on 285 probands with bipolar disorder and their parents were drawn from families in the NIMH Genetics Initiative consortium for bipolar disorder (NIMH1-4) and two other series. Fine scale mapping using one family series (NIMH1-2) as the test sample was targeted on a gene that displayed the highest evidence of association. A secondary analysis of familial component phenotypes of bipolar disorder was conducted.
  
  
  RESULTS
  Three of seven SNPs in DOCK9, a gene that encodes an activator of the Rho-GTPase Cdc42, showed significant excess allelic transmission (P=0.0477-0.00067). Fine scale mapping on DOCK9 yielded evidence of association at nine SNPs in the gene (P=0.02-0.006). Follow-up tests detected excess transmission of the same allele of rs1340 in two out of three other sets of families. The association signals were largely attributable to maternally transmitted alleles (rs1927568: P=0.000083; odds ratio=3.778). A secondary analysis of familial component phenotypes of bipolar disorder detected significant association across multiple DOCK9 markers for racing thoughts, psychosis, delusion during mania and course of illness indicators.
  
  
  CONCLUSIONS
  These results suggest that DOCK9 contributes to both risk and increased illness severity in bipolar disorder. We found evidence for the effect of phenotypic heterogeneity on association. To our knowledge this is the first report to implicate DOCK9 or the Rho-GTPase pathway in the etiology of bipolar disorder.
authors.affiliation: Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health/U.S. DHHS, 35 Convent Drive, Bethesda, MD 20892, USA. deteras@mail.nih.gov
authors.forename: Sevilla D
authors.initials: SD
authors.lastname: Detera-Wadleigh
authors.forename: Chun-yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Manjula
authors.initials: M
authors.lastname: Maheshwari
authors.forename: Imer
authors.initials: I
authors.lastname: Cardona
authors.forename: Winston
authors.initials: W
authors.lastname: Corona
authors.forename: Nirmala
authors.initials: N
authors.lastname: Akula
authors.forename: C J M
authors.initials: CJ
authors.lastname: Steele
authors.forename: Judith A
authors.initials: JA
authors.lastname: Badner
authors.forename: Mukta
authors.initials: M
authors.lastname: Kundu
authors.forename: Layla
authors.initials: L
authors.lastname: Kassem
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Gershon
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
chemical_list: C466321:DOCK9 protein, human; D020662:Guanine Nucleotide Exchange Factors