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Human Molecular Genetics Advance Access published online on December 12, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm368
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Association of NFKB1, which encodes a subunit of the transcription factor NF-{kappa}B, with Alcohol Dependence

Howard J. Edenberg*,1, Xiaoling Xuei1, Leah Flury Wetherill1, Laura Bierut2, Kathleen Bucholz2, Danielle M. Dick2, Victor Hesselbrock3, Sam Kuperman4, Bernice Porjesz5, Marc A. Schuckit6, Jay A. Tischfield7, Laura A. Almasy8, J. I. Nurnberger, Jr.1 and Tatiana Foroud1

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

* Corresponding author Dr. Howard J. Edenberg Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr, MS4063, Indianapolis, IN 46202-5122, Phone: 317-274-2353, Fax: 317-274-4686, E-mail: edenberg{at}iupui.edu

Received August 2, 2007; Revised November 19, 2007; Accepted December 10, 2007

A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism. NFKB1 encodes a 105 kDa transcription inhibitor that is cleaved to the 50 kDa DNA binding subunit of the ubiquitous transcription factor NF-{kappa}B. NF-{kappa}B regulates many genes relevant to brain function, and its actions can be potentiated by ethanol; thus NFKB1 is an excellent candidate gene for alcoholism. Nineteen SNPs in and near NFKB1 were analyzed in a sample of 219 multiplex alcoholic families of European American descent. Family based association analyses detected significant evidence of association with eight SNPs and marginal evidence for five more. The association was driven by the affected individuals with earlier onset of alcoholism (55% of the sample with onset ≤21 years). Further analysis of the age of onset as a quantitative variable provided evidence for the association of 12 SNPs in this gene. Thus variations in NFKB1 appear to affect the risk for alcoholism, particularly contributing to an earlier onset of the disease.


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