Association of NFKB1, which encodes a subunit of the transcription factor NF-kappaB, with alcohol dependence.
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-kappaB. NF-kappaB 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 < or =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.
Edenberg
Howard J
HJ
Indiana University School of Medicine, Indianapolis, IN, USA. edenberg@iupui.edu
Xuei
Xiaoling
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Wetherill
Leah Flury
LF
Bierut
Laura
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Bucholz
Kathleen
K
Dick
Danielle M
DM
Hesselbrock
Victor
V
Kuperman
Sam
S
Porjesz
Bernice
B
Schuckit
Marc A
MA
Tischfield
Jay A
JA
Almasy
Laura A
LA
Nurnberger
J I
JI
Foroud
Tatiana
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D017668:Age of Onset; D000437:Alcoholism / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4; D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D016328:NF-kappa B / Q000235:genetics*; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D014481:United States; D044465:White People
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D014157:Transcription Factors