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Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies.

ABSTRACT: 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.

SUBMITTER: Philibert RA

PROVIDER: S-EPMC3643116 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies.

Philibert Robert A RA Gunter Tracy D TD Beach Steven R H SR Brody Gene H GH Hollenbeck Nancy N Andersen Allan A Adams William W

Psychiatric genetics 20090401 2

<h4>Aim</h4>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.<h4>Objective</h4>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 GA ...[more]

PMID: 19672139

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Project description:BACKGROUND:Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the ?-aminobutyric acid A (GABA(A)) receptor ?2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration. METHODS:One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 ± 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis. RESULTS:Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence-associated allele regardless of ALDH2 genotype. CONCLUSIONS:These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.

Dataset Information

Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies.

Publications

Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies.

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