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Human Molecular Genetics Advance Access originally published online on December 21, 2006
Human Molecular Genetics 2007 16(4):380-390; doi:10.1093/hmg/ddl460
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans

Xingguang Luo1,3, Henry R. Kranzler4, Lingjun Zuo1,3, Shuang Wang5, Nicholas J. Schork6 and Joel Gelernter1,2,3,7,*

1 Department of Psychiatry and 2 Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA, 3 VA Connecticut Healthcare System, West Haven, CT, USA, 4 Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, CT, USA, 5 Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA, 6 Department of Psychiatry, University of California School of Medicine, San Diego, La Jolla, CA, USA and 7 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

* To whom correspondence should be addressed at:, Yale University School of Medicine, VA Psychiatry 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA. Tel: +1 203932 5711 ext. 3590; Fax: +1 2039373897; Email: joel.gelernter{at}yale.edu

Received October 13, 2006; Accepted December 6, 2006

Drug dependence (DD) is commonly co-morbid with alcohol dependence (AD). Many studies have also shown common genetic risk factors for these disorders. We previously reported associations of AD with seven alcohol dehydrogenase (ADH) genes. The present study examines the relationship between these genes and DD. We genotyped 16 markers within the ADH gene cluster and 38 unlinked ancestry-informative markers in a case–control sample of 718 individuals. All markers were consistent with Hardy–Weinberg equilibrium in controls, but some markers showed Hardy–Weinberg disequilibrium in cases (minimal P = 0.002). Genotypes of many markers were associated with DD, both before and after controlling for admixture effects (minimal P < 1.0 x 10–6). Diplotype trend regression analysis showed that ADH5 and ADH6 genotypes, and diplotypes at ADH1A, ADH1B, ADH1C and ADH7 (minimal P = 0.002), were associated with DD in European-Americans and/or African-Americans. This first report of an allelic association of these loci with DD provides new insight into the mechanism of genetic risk for DD. These findings, obtained using a series of powerful and reliable analytic methods, may also help to explain the high rate of co-morbidity between AD and DD.


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