Human Molecular Genetics Advance Access originally published online on December 12, 2007
Human Molecular Genetics 2008 17(7):963-970; doi:10.1093/hmg/ddm368
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Association of NFKB1, which encodes a subunit of the transcription factor NF-
B, with alcohol dependence
1 Indiana University School of Medicine, Indianapolis, IN, USA 2 Washington University School of Medicine, St Louis, MO, USA 3 University of Connecticut, Farmington, CT, USA 4 University of Iowa Carver College of Medicine, Iowa City, IA, USA 5 SUNY Health Sciences Center, Brooklyn, NY, USA 6 University of California, San Diego, CA, USA 7 Rutgers University, Piscataway, NJ, USA 8 Southwest Foundation for Biomedical Research, San Antonio, TX, USA
* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS4063, Indianapolis, IN 46202-5122, USA. Tel: + 1 3172742353; Fax: + 1 3172744686; Email: 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-
B. NF-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.