Sequence variation in DOCK9 and heterogeneity in bipolar disorder.

TitleSequence variation in DOCK9 and heterogeneity in bipolar disorder.
Publication TypeJournal Article
Year of Publication2007
AuthorsDetera-Wadleigh, SD, Liu, C-yu, Maheshwari, M, Cardona, I, Corona, W, Akula, N, Steele, CJM, Badner, JA, Kundu, M, Kassem, L, Potash, JB, Gibbs, R, Gershon, ES, McMahon, FJ
Corporate Authors
JournalPsychiatr Genet
Volume17
Issue5
Pagination274-86
Date Published2007 Oct
ISSN0955-8829
KeywordsBipolar Disorder, Family, Female, Genetic Predisposition to Disease, Genetic Variation, Guanine Nucleotide Exchange Factors, Humans, Linkage Disequilibrium, Male, Phenotype, Polymorphism, Single Nucleotide, Severity of Illness Index
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.CONCLUSION: 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.

DOI10.1097/YPG.0b013e328133f352
Alternate JournalPsychiatr. Genet.
PubMed ID17728666
Grant List1Z01 MH 002810-01 / MH / NIMH NIH HHS / United States
MH 59533 / MH / NIMH NIH HHS / United States
R01 MH 059548 / MH / NIMH NIH HHS / United States
R01 MH 059556 / MH / NIMH NIH HHS / United States
R01 MH 59534 / MH / NIMH NIH HHS / United States
R01 MH 59535 / MH / NIMH NIH HHS / United States
R01 MH 59545 / MH / NIMH NIH HHS / United States
R01 MH 59553 / MH / NIMH NIH HHS / United States
R01 MH 59567 / MH / NIMH NIH HHS / United States
R01 MH 60068 / MH / NIMH NIH HHS / United States
/ / Intramural NIH HHS / United States