Journal
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS
Volume 129B, Issue 1, Pages 104-109Publisher
WILEY
DOI: 10.1002/ajmg.b.30091
Keywords
psychiatric genetics; GABA(A) receptor; GABRA2; alcohol dependence
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Funding
- NCRR NIH HHS [M01-RR06192] Funding Source: Medline
- NIAAA NIH HHS [P50-AA03510, R01-AA11330, K24-AA13736] Funding Source: Medline
- NIDA NIH HHS [K24-DA15105] Funding Source: Medline
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Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABA(A) neurotransmitter receptor is an important mediator for several behavioral effects of alcohol, genes encoding GABA-related proteins are functional candidates to influence risk of alcohol dependence. Two genome-wide scans showed linkage of alcohol dependence to a region on chromosome 4p, which contains a cluster of genes encoding GABA(A) receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABA(A) receptor alpha-2 subunit (GABRA2). We examined 10 single nucleotide polymorphisms (SNPs) spanning the coding region of this gene in samples of European American subjects with alcohol dependence (n = 446), and controls (n = 334) screened to exclude substance use disorders. There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 lip in the middle and 3'-portion of the GABRA2 gene (range of P-values = 0.008-0.03). When the subset of the alcohol-dependent subjects excluding those with a diagnosis of cocaine or opioid dependence or major depressive episode (n = 198) was examined, the strength of the association was increased across these 7 SNPs (range of P-values = 0.002-0.007). Two common haplotypes in this region accounted for 90.8% of chromosomes. The more common haplotype was present in 55.6% of control group chromosomes versus 48.2% of alcohol-dependent subjects (P = 0.007) and 45.8% of subjects with alcohol dependence but no co-morbid drug dependence or depression (P = 0.003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence. (C) 2004 Wiley-Liss, Inc.
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