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Human Molecular Genetics Advance Access published online on March 28, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl073
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© The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received January 18, 2006
Revised March 22, 2006
Accepted March 22, 2006

Article

Association of Alcohol Dehydrogenase Genes with Alcohol Dependence: a comprehensive analysis

Howard J. Edenberg 1 *, Xiaoling Xuei 1, Hui-Ju Chen 1, Huijun Tian 1, Leah Flury Wetherill 1, Danielle M. Dick 2, Laura Almasy 3, Laura Bierut 2, Kathleen K. Bucholz 2, Alison Goate 2, Victor Hesselbrock 4, Samuel Kuperman 5, John Nurnberger 1, Bernice Porjesz 6, John Rice 2, Marc Schuckit 7, Jay Tischfield 8, Henri Begleiter 6, and Tatiana Foroud 1

1 Indiana University School of Medicine, Indianapolis, IN
2 Washington University School of Medicine, St. Louis, MO
3 Southwest Foundation for Biomedical Research, San Antonio, TX
4 University of Connecticut, Farmington, CT
5 University of Iowa Carver College of Medicine, Iowa City, IA
6 SUNY Health Sciences Center, Brooklyn, NY
7 University of California, San Diego, CA
8 Rutgers University, Piscataway, NJ

* To whom correspondence should be addressed.
Howard J. Edenberg, E-mail: edenberg{at}iupui.edu


  Abstract

Linkage evidence indicated that gene(s) located on chromosome 4q, in the region of the alcohol dehydrogenase (ADH) genes, affected risk for alcoholism. We genotyped 110 SNPs across the 7 ADH genes and analyzed their association with alcoholism in a set of families with multiple alcoholic members, using the Pedigree Disequilibrium Test. There was strong evidence that variations in ADH4 are associated with alcoholism: 12 SNPs were significantly associated. The region of strongest association ran from intron 1 to 19.5 kb beyond the 3' end of the gene. Haplotype tag SNPs were selected for the block in the ADH4 gene that provided evidence of association and subsequently used in association analyses; the haplotypes were significantly associated with alcoholism (p = 0.01) There was weaker evidence that variations in ADH1A and ADH1B might also play a role in modifying risk. Among African Americans, there was evidence that the ADH1B*3 allele was protective.


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