A number of studies have shown that genetic variation at GABRA2 alters vulnerability to alcohol dependence. The exact identity of the causal variant(s), and the relationship of these variants to other forms of substance use and behavioral illness is, however, uncertain.
Therefore, we genotyped 516 individuals from the Iowa Adoption Studies, a large longitudinal case and control adoption study of substance use, at 39 single nucleotide polymorphisms encompassing the GABRA2 locus and analyzed them with respect to their lifetime history of three common forms of substance use dependence [alcohol dependence (AD), nicotine dependence (ND), and cannabis dependence (CD)] in the Iowa Adoption Studies and relevant exposure variables.
Using regression analysis, we found substantial evidence that both GABRA2 genotype and haplotype are significantly related to vulnerability to AD, ND, and CD, with the strongest relationships noted with respect to ND. Consistent with earlier studies suggesting exposure is an important step in the development of substance use, we found the inclusion of substance exposure data in our analytic models markedly increased the strength of the genetic associations of GABRA2 haplotype with substance use. Finally, we report that the genetic effects were markedly more pronounced in females than in males.
We conclude that genetic variation at or near the GABRA2 locus significantly affects vulnerability not only to AD, but to other forms of substance use including ND and CD, and that the effects may be sex dependent.
aDepartment of Psychiatry
bNeuroscience and Genetics Programs, The University of Iowa, Iowa City, Iowa
cGeorgetown University, Washington, DC
dUniversity of Georgia, Athens, Georgia, USA
Correspondence to Robert A. Philibert, MD, PhD, Department of Psychiatry, Rm 2-126 MEB Psychiatry Research/MEB, Iowa City, IA 52242-1000, USA
Tel: +1 319 353 4986; fax: +1 301 353 3003;
Received 16 January 2008 Revised 9 September 2008 Accepted 23 October 2008