Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies.
- Authors
- Philibert, Robert A; Gunter, Tracy D; Beach, Steven R H; Brody, Gene H; Hollenbeck, Nancy; Andersen, Allan; Adams, William
- Year
- 2009
- Journal
- Psychiatric genetics
- PMID
- 19672139
- DOI
- 10.1097/YPG.0b013e3283208026
- PMCID
- PMC3643116
AIM: 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. OBJECTIVE: 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. RESULT: 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. CONCLUSION: 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.
The position of each of the SNP markers relative to the intron-exon structure of GABRA2 and the amount of linkage disequilibrium (D′) between the markers as per Haploview [18]. Please note that due to distortions of scale necessary for visualization of the placement of the exons, that some markers erroneously appear to be in the coding sections of GABRA2. Only rs279858 (exon 5) and rs573400 (exon 10) are actually in the coding sections of GABARA2. In order to improve visual clarity, all D′ values are shown here multiplied × 100 as to avoid the necessity to display decimal points. The D′ value in blocks without numbers is 1.00.
SNP Haplotypes and their frequency as imputed using data from all 35 SNPs. The yellow lines designate the four SNPs used to form the haplotypes used in the analyses.
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