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Genetic association of bipolar disorder with the β3 nicotinic receptor subunit gene

Hartz, Sarah M.a; Lin, Penga; Edenberg, Howard J.j; Xuei, Xiaolingj; Rochberg, Nanettea; Saccone, Scotta; Berrettini, Wadeg; Nelson, Elliota; Nurnberger, Johnk; Bierut, Laura J.a; Rice, John P.a

doi: 10.1097/YPG.0b013e32834135eb
Original Articles

Objective Owing to the clinical relationship between bipolar disorder and nicotine dependence, we investigated two research questions: (i) are genetic associations with nicotine dependence different in individuals with bipolar disorder as compared with individuals without bipolar disorder, and (ii) do loci earlier associated with nicotine dependence have pleiotropic effects on these two diseases.

Method Our study consisted of 916 cases with bipolar disorder and 1028 controls. On the basis of known associations with nicotine dependence, we genotyped eight single-nucleotide polymorphisms (SNPs) on chromosome 8 (three bins) in the regions of CHRNB3 and CHRNA6, and six SNPs on chromosome 15 (three bins) in the regions of CHRNA5 and CHRNA3.

Results To determine whether the genetic associations with nicotine dependence are different in bipolar disorder than in the general population, we compared allele frequencies of candidate SNPs between individuals with nicotine dependence only and individuals with both nicotine dependence and bipolar disorder. There were no statistical differences between these frequencies, indicating that genetic association with nicotine dependence is similar in individuals with bipolar disorder as in the general population. In the investigation of pleiotropic effects of these SNPs on bipolar disorder, two highly correlated synonymous SNPs in CHRNB3, rs4952 and rs4953, were significantly associated with bipolar disorder (odds ratio 1.7, 95% confidence interval: 1.2–2.4, P=0.001). This association remained significant both after adjusting for a smoking covariate and analyzing the association in nonsmokers only.

Conclusion Our results suggest that (i) bipolar disorder does not modify the association between nicotine dependence and nicotinic receptor subunit genes, and (ii) variants in CHRNB3/CHRNA6 are independently associated with bipolar disorder.

aDepartment of Psychiatry, Washington University School of Medicine, St Louis, Missouri

bDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore

cLaboratory of Clinical Science

dUnit on the Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland

eDepartment of Psychiatry, University of California, Irvine

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

gUniversity of Pennsylvania, Philadelphia, Pennsylvania

hDepartment of Psychiatry, Rush University Medical Center, Chicago, Illinois

iDepartment of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa

Departments of jBiochemistry and Molecular Biology

kPsychiatry, Indiana University School of Medicine, Indianapolis, Indiana

lDepartment of Psychiatry, Howard University, Washington, DC, USA

Correspondence to John P. Rice, PhD, Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA Tel: +1 314 286 2572; fax: +1 314 286 2577; e-mail:

Received January 6, 2010

Accepted June 20, 2010

© 2011 Lippincott Williams & Wilkins, Inc.