Um estudo de ampla associação genômica da dependência de álcool

quarta-feira, março 03, 2010

A genome-wide association study of alcohol dependence

Laura J. Bierut a,1, Arpana Agrawal a, Kathleen K. Bucholz a, Kimberly F. Doheny b, Cathy Laurie c, Elizabeth Pugh b, Sherri Fisher a, Louis Fox a, William Howells a, Sarah Bertelsen a, Anthony L. Hinrichs a, Laura Almasy d, Naomi Breslau e, Robert C. Culverhouse f, Danielle M. Dick g, Howard J. Edenberg h, Tatiana Foroud i, Richard A. Grucza a, Dorothy Hatsukami j, Victor Hesselbrock k, Eric O. Johnson l, John Kramer m, Robert F. Krueger a, Samuel Kuperman n, Michael Lynskey a, Karl Mann o, Rosalind J. Neuman a, Markus M. Nöthen p, John I. Nurnberger Jr. q, Bernice Porjesz r, Monika Ridinger s, Nancy L. Saccone t, Scott F. Saccone a, Marc A. Schuckit u, Jay A. Tischfield v, Jen C. Wang a, Marcella Rietschel w, Alison M. Goate a, John P. Rice a, and as part of the Gene, Environment Association Studies (GENEVA) Consortium

+Author Affiliations

aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110;
bCenter for Inherited Disease Research, Johns Hopkins Medical Center, Baltimore, MD 21224;
cDepartment of Biostatistics, University of Washington, Seattle, WA, 98195;
dDepartment of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78245;
eDepartment of Epidemiology, Michigan State University, East Lansing, MI 48824;
fDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
gVirginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298;
hDepartment of Biochemistry and Molecular Biology, and
iDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202;
jTobacco Research Center, University of Minnesota, Minneapolis, MN, 55415;
kDepartment of Psychiatry, University of Connecticut, Farmington, CT 06030;
lDivision of Health, Social and Economic Research, Research Triangle Institute International, Research Triangle Park, NC 27709;
mDepartment of Psychiatry, University of Iowa College of Medicine, Iowa City, IA 52242;
nDivision of Child Psychiatry, University of Iowa Hospitals, Iowa City, IA 52242;
oDepartment of Addictive Behavior and Addictive Medicine, Central Institute of Mental Health, Mannheim, Germany;
pDepartment of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany;
qDepartment of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202;
rDepartment of Psychiatry, State University of New York, Brooklyn, NY 11203;
sDepartment of Psychiatry, Mental State Hospital, University of Regensburg, Regensburg, Germany;
tDepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110;
uDepartment of Psychiatry, University of California-San Diego, La Jolla, CA 92037;
vDepartment of Genetics, Rutgers University, Piscataway, NJ, 08854; and
wDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany

Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved February 2, 2010 (received for review September 25, 2009)

Abstract

Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10−5, but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor α2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.

genetics   candidate genes

Footnotes

1To whom correspondence should be addressed. E-mail:bierutl@psychiatry.wustl.edu.

Author contributions: L.J.B., K.K.B., A.L.H., H.J.E., A.M.G., and J.P.R. designed research; L.J.B., K.K.B., K.F.D., S.F., N.B., D.H., V.H., E.O.J., J.K., S.K., K.M., M.M.N., J.I.N., B.P., M. Ridinger, J.A.T., and J.P.R. performed research; K.M. contributed new reagents/analytic tools; L.J.B., A.A., C.L., E.P., L.F., W.H., S.B., M. Rietschel, and J.P.R. analyzed data; and L.J.B., A.A., K.K.B., K.F.D., C.L., E.P., S.F., L.F., W.H., S.B., A.L.H., L.A., N.B., R.C.C., D.M.D., H.J.E., T.F., R.A.G., D.H., V.H., E.O.J., J.K., R.F.K., S.K., M.L., R.J.N., J.I.N., B.P., N.L.S., S.F.S., M.A.S., J.A.T., J.C.W., M. Rietschel, A.M.G., and J.P.R. wrote the paper.

Conflict of Interest Statement: L.J.B., J.P.R., A.M.G., S.F.S., and J.C.W. are inventors on the patent “Markers for Addiction” (US 20070258898) covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. N.L.S. is the spouse of S. F.S., who is listed as an inventor on the patent. L.J.B. served as a consultant for Pfizer Inc. in 2008.

This article is a PNAS Direct Submission.

Data deposition: Data can be obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000092.v1.p1 through dbGaP accession number phs000092.v1.p1.

This article contains supporting information online at www.pnas.org/cgi/content/full/0911109107/DCSupplemental.

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