1. ¹Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, CT, USA
2. ²Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA
3. ³Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA

Correspondence: Dr J Covault, Department of Psychiatry, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1410, USA. Tel: +1 860 679 7560; Fax: +1 860 679 1296; E-mail: jocovault@uchc.edu

Received 26 January 2007; Revised 27 March 2007; Accepted 17 April 2007; Published online 16 May 2007.

Abstract

Following an initial report, there have been multiple replications of an association of alcohol dependence (AD) to markers within a haplotype block that includes the 3'-half of the gene encoding the GABA_A -2 subunit (GABRA2), on chromosome 4p. We examined the intergenic extent of this haplotype block and the association to AD of markers in the adjacent 5' haplotype block in GABRG1, which encodes the GABA_A receptor -1 subunit. We genotyped 15 single nucleotide polymorphisms in the GABRG1-GABRA2 interval as well as at 34 ancestry informative markers in three samples: 435 AD and 635 screened control subjects from Connecticut and 812 participants from a multicenter AD treatment trial. We observed two large haplotype blocks in the GABRG1-GABRA2 intergenic interval with a region of increased recombination midway between the two genes. Markers in the two haplotype blocks were in moderate linkage disequilibrium. Compared with markers in the GABRA2 haplotype block, markers in the 5' GABRG1 haplotype showed greater allelic, genotypic and haplotypic association with AD in European Americans from both AD samples. Logistic regression analysis indicated that genetic elements in the GABRG1 haplotype block likely contribute to AD risk in an additive manner, whereas those in the GABRA2 haplotype block may act in a dominant manner in relation to risk of AD.