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Genome-wide parametric linkage analyses of 644 bipolar pedigrees suggest susceptibility loci at chromosomes 16 and 20

Ross, Jessicaa; Berrettini, Wadeb; Coryell, Williamc; Gershon, Elliot S.d; Badner, Judith A.d; Kelsoe, John R.f; McInnis, Melvin G.g; McMahon, Francis J.h; Murphy, Dennis L.i; Nurnberger, John I. Jrj; Foroud, Tatianak; Rice, John P.m; Scheftner, William B.e; Zandi, Petern; Edenberg, Howardl; Byerley, Williama

doi: 10.1097/YPG.0b013e3283050aa5
Original Articles

Objective Our aim is to map chromosomal regions that harbor loci that increase susceptibility to bipolar disorder.

Methods We analyzed 644 bipolar families ascertained by the National Institute of Mental Health Human Genetics Initiative for bipolar disorder. The families have been genotyped with microsatellite loci spaced every approximately 10 cM or less across the genome. Earlier analyses of these pedigrees have been limited to nonparametric (model-free) methods and thus, information from unaffected subjects with genotypes was not considered. In this study, we used parametric analyses assuming dominant and recessive transmission and specifying a maximum penetrance of 70%, so that information from unaffecteds could be weighed in the linkage analyses. As in previous linkage analyses of these pedigrees, we analyzed three diagnostic categories: model 1 included only bipolar I and schizoaffective, bipolar cases (1565 patients of whom approximately 4% were schizoaffective, bipolar); model 2 included all individuals in model 1 plus bipolar II patients (1764 total individuals); and model 3 included all individuals in model 2 with the addition of patients with recurrent major depressive disorder (2046 total persons).

Results Assuming dominant inheritance the highest genome-wide pair-wise logarithm of the odds (LOD) score was 3.2 with D16S749 using model 2 patients. Multipoint analyses of this region yielded a maximum LOD score of 4.91. Under recessive transmission a number of chromosome 20 markers were positive and multipoint analyses of the area gave a maximum LOD of 3.0 with model 2 cases.

Conclusion The chromosome 16p and 20 regions have been implicated by some studies and the data reported herein provide additional suggestive evidence of bipolar susceptibility genes in these regions.

aDepartment of Psychiatry, University of California, San Francisco

bDepartment of Psychiatry, University of Pennsylvania

cDepartment of Psychiatry, University of Iowa, USA

dDepartment of Psychiatry, University of Chicago, Chicago

eDepartment of Psychiatry, Rush University, Illinois

fDepartment of Psychiatry, University of California – San Diego, California

gDepartment of Psychiatry, University of Michigan

hGenetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Program, National Institute of Mental Health Intramural Research Program, US Department of Health and Human Service

iLaboratory of Clinical Science, National Institute of Mental Health Intramural Research Program, Department of Health and Human Services

jDepartments of Psychiatry

kMedical and Molecular Genetics

lBiochemistry and Molecular Biology and of Medical and Molecular Genetics, Indiana University School of Medicine

mDepartment of Psychiatry, Washington University, Washington

nDepartment of Psychiatry, Johns Hopkins University, Maryland, USA

Correspondence to William Byerley, Langley Porter Psychiatric Institute, 401 Parnassus, University of California–San Francisco, San Francisco, CA 94132-0984, USA

Tel: +1 415 476 7432; fax: +1 415 476 7320; e-mail:

Received 26 March 2007 Revised 10 September 2007 Accepted 26 September 2007

© 2008 Lippincott Williams & Wilkins, Inc.