Allelic and haplotypic association of GABRA2 with alcohol dependence

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Neuropsychiatric genetics, 2004-08, Vol.129B (1), p.104-109
• Main Authors: Covault, Jonathan, Gelernter, Joel, Hesselbrock, Victor, Nellissery, Maggie, Kranzler, Henry R.
• Format: Article
• Language: English
• Subjects: Adult; alcohol dependence; Alcoholism - genetics; Alleles; Chromosomes, Human, Pair 4 - genetics; DNA - chemistry; DNA - genetics; DNA Mutational Analysis; Female; GABA(A) receptor; GABRA2; Gene Frequency; Genotype; Haplotypes; Humans; Male; Middle Aged; Multigene Family - genetics; Polymorphism, Single Nucleotide; Protein Subunits - genetics; psychiatric genetics; Receptors, GABA-A - genetics
• ISSN: 1552-4841; 1552-485X
• DOI: 10.1002/ajmg.b.30091

Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABAA 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 GABAA receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABAA receptor α‐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 bp 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. © 2004 Wiley‐Liss, Inc.