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Haplotype-Based Localization of an Alcohol Dependence Gene to the 5q34 -Aminobutyric Acid Type A Gene Cluster

Marta Radel, MD, PhD; Roger L. Vallejo, PhD; Nakao Iwata, MD, PhD; Richard Aragon, PhD; Jeffrey C. Long, PhD; Matti Virkkunen, MD; David Goldman, MD

Arch Gen Psychiatry. 2005;62:47-55.

Context  Pharmacobehavioral and pharmacogenetic evidence links -aminobutyric acid type A (GABA_A) receptors and chromosomal regions containing GABA_A receptor genes to ethanol-related responses. The GABA_A gene cluster on chromosome 5q34 is of particular interest in the genetics of alcohol dependence because of the 2 subunit requirement for ethanol’s modulatory action on GABA_A receptors, previous linkage findings in mice and humans implicating both GABRA6 and GABRG2, and reported associations of GABRA6, GABRB2, and GABRG2 alleles with alcohol dependence.

Objective  To determine whether variation at the 5q34 GABA_A gene cluster is implicated in differential susceptibility to alcohol dependence.

Methods  Two large psychiatrically interviewed samples, a Southwestern Native American population sample (N = 433) and a Finnish sample (N = 511) with alcohol-dependent subjects and unaffected individuals, were genotyped for 6 single nucleotide polymorphisms at the 5q34 GABA_A gene cluster. In addition to sib-pair linkage and case-control association analyses, linkage disequilibrium mapping with haplotypes was used.

Results  Sib-pair linkage of GABRG2 to alcohol dependence was observed in Finns (P = .008). Association of the GABRB2 1412T allele with alcohol dependence was detected in both populations (Finns, P = .01; Southwestern Native Americans, P = .008), and the GABRA6 1519T allele was associated in both Finns (P = .01) and Southwestern Native Americans (P = .03). Linkage disequilibrium mapping with 3-locus haplotypes yielded evidence for an alcohol-dependence locus at the GABA_A gene cluster region in both populations. The most highly significant signals were at 3-locus haplotypes that included 1 or more GABRA6 polymorphisms, with the peak signal at a GABRA6 3-locus haplotype (Finns, empirical P = .004; Southwestern Native Americans, empirical P = .02).

Conclusions  We detected sib-pair linkage of 5q34 GABA_A receptor genes to alcohol dependence in Finns and found association both in Finns and in Southwestern Native Americans. In both populations, the haplotype localization implicates the region containing the Pro385Ser GABRA6 polymorphism and 2 other polymorphisms at GABRA6.

Author Affiliations: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Md (Drs Radel, Vallejo, Aragon, Long, and Goldman); Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan (Dr Iwata); and Department of Psychiatry, University of Helsinki, Helsinki, Finland (Dr Virkkunen).

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