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Sequence variation in DOCK9 and heterogeneity in bipolar disorder

Detera-Wadleigh, Sevilla D.a; Liu, Chun-yuc; Maheshwari, Manjulad; Cardona, Imera; Corona, Winstona; Akula, Nirmalaa; Steele, C.J.M.a; Badner, Judith A.c; Kundu, Muktaa; Kassem, Laylaa; Potash, James B.b; Gibbs, Richardd; Gershon, Elliot S.c; McMahon, Francis J.aNIMH Genetics Initiative for Bipolar Disorder Consortium

doi: 10.1097/YPG.0b013e328133f352
ORIGINAL ARTICLES

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.

aGenetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda

bDepartment of Psychiatry, Johns Hopkins University, Baltimore, Maryland

cDepartment of Psychiatry, University of Chicago, Chicago, Illinois

dDepartment of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas

eIndiana University, Indianapolis, Indianapolis

fWashington University, St Louis, Missouri

gUniversity of Pennsylvania, Philadelphia, Pennsylvania

hUniversity of California at Irvine, California

iUniversity of Iowa, Iowa

jUniversity of California at San Diego, California

kRush University, Illinois, USA

Correspondence to Sevilla D. Detera-Wadleigh, MAP, NIMH, NIH, Building 35 Room 1A205, 35 Convent Drive, Bethesda, MD 20892-3719, USA

Tel: +1 301 496 8089; fax: +1 301 402 9081;

e-mail: deteras@mail.nih.gov

Received 18 December 2006 Revised 31 January 2007 Accepted 5 February 2007

© 2007 Lippincott Williams & Wilkins, Inc.