Please cite this article as follows: Enoch M-A, Schwartz L, Albaugh B, Virkkunen M, Goldman D. 2006. Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism. Am J Med Genet Part B 141B:599–607.
Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism†
Article first published online: 27 JUL 2006
Copyright © 2006 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 141B, Issue 6, pages 599–607, 5 September 2006
How to Cite
Enoch, M.-A., Schwartz, L., Albaugh, B., Virkkunen, M. and Goldman, D. (2006), Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism. Am. J. Med. Genet., 141B: 599–607. doi: 10.1002/ajmg.b.30336
- Issue published online: 17 AUG 2006
- Article first published online: 27 JUL 2006
- Manuscript Accepted: 22 MAR 2006
- Manuscript Received: 27 JUL 2005
- American Indian;
- harm avoidance
The GABAAα2 receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite-configuration haplotypes in the region distal to intron3 predict risk. We have now replicated the GABRA2 association with alcoholism in 331 Plains Indian men and women and 461 Finnish Caucasian men. Using a dimensional measure of anxiety, harm avoidance (HA), we also found that the association with alcoholism is mediated, or moderated, by anxiety. Nine SNPs were genotyped revealing two haplotype blocks. Within the previously implicated block 2 region, we identified the two common, opposite-configuration risk haplotypes, A and B. Their frequencies differed markedly in Finns and Plains Indians. In both populations, most block 2 SNPs were significantly associated with alcoholism. The associations were due to increased frequencies of both homozygotes in alcoholics, indicating the possibility of alcoholic subtypes with opposite genotypes. Congruently, there was no significant haplotype association. Using HA as an indicator variable for anxiety, we found haplotype linkage to alcoholism with high and low dimensional anxiety, and to HA itself, in both populations. High HA alcoholics had the highest frequency of the more abundant haplotype (A in Finns, B in Plains Indians); low HA alcoholics had the highest frequency of the less abundant haplotype (B in Finns, A in Plains Indians) (Finns: P = 0.007, OR = 2.1, Plains Indians: P = 0.040, OR = 1.9). Non-alcoholics had intermediate frequencies. Our results suggest that within the distal GABRA2 region is a functional locus or loci that may differ between populations but that alters risk for alcoholism via the mediating action of anxiety. © 2006 Wiley-Liss, Inc.