Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism

Abstract

The GABAAα 2 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 α0.007, OR α2.1, Plains Indians: P α0.040, OR α1.9). 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.

Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations

“…Our previous study in these two populations has shown that alcoholics with high HA, defined as X the population mean (taken as the mean HA for nonalcoholics), and low HA, defined as < the population mean, may be distinct subtypes. 31 In the current study, we only found a nonsignificant trend for the association of HA with GAL haplotypes and diplotypes in alcoholics. Nevertheless, because our study has no precedent, we decided to pursue exploratory analyses of the HA association.…”

“…The sample from Helsinki, Finland, has been described in detail elsewhere. 30,31 In total, 514 men were genotyped: 263 alcoholics and 251 nonalcoholics. Written informed consent was obtained according to human research protocols approved by the human research committees of NIAAA and NIMH, NIH, the Department of Psychiatry, University of Helsinki, and the University of Helsinki Central Hospital, Helsinki, Finland.…”

The role of GABAA receptors in the development of alcoholism

“…Another issue may be sexual dimorphism. As described above, Enoch et al (2006) found significant anxiety-mediated GABRA2 haplotype associations with alcoholism in Finnish Caucasian and American Indian men but found no association in American Indian women. The negative study in African Americans (Covault et al, 2008) may be attributable to the fact that in this group the two yin yang risk haplotypes are present at much lower frequencies (29% and 27%) compared with other populations (Enoch, unpublished data; Figure 3).…”

“…Alcoholics, including those with antisocial personality disorder, have been shown to have higher trait anxiety than non-alcoholics (Ducci et al, 2007;Goodwin and Hamilton, 2003). If trait anxiety does indeed play a role in mediating linkage of GABRA2 haplotypes with alcoholism then the Enoch et al (2006) study would predict that COGA alcoholics have higher trait anxiety than the treatment seeking alcoholics of other studies (Covault et al, 2004;Fehr et al, 2006;Lappalainen et al, 2005). Indeed, it has been demonstrated that COGA alcoholics have higher trait anxiety than non-alcoholics (Ducci et al, 2007).…”

“…Supportive evidence for this apparent paradox comes from a study in non-treatment seeking alcoholics in two population isolates, Finnish Caucasians and Plains American Indians (Enoch et al, 2006). This study showed that although there was no haplotype association with alcoholism per se, alcoholics with high trait anxiety (TPQ harm avoidance) had the highest frequency of the more abundant haplotype, alcoholics with low anxiety had the highest frequency of the less abundant haplotype and non-alcoholics had intermediate frequencies (Enoch et al, 2006). Alcoholics, including those with antisocial personality disorder, have been shown to have higher trait anxiety than non-alcoholics (Ducci et al, 2007;Goodwin and Hamilton, 2003).…”