Enoch Mary-Anne, Schwartz Lori, Albaugh Bernard, Virkkunen Matti, Goldman David
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland 20892, USA.
Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141B(6):599-607. doi: 10.1002/ajmg.b.30336.
The GABAAalpha2 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.
γ-氨基丁酸A型α2受体基因（GABRA2）调节焦虑和应激反应。最近的三项关联研究表明GABRA2与酒精中毒有关，然而在这些论文中，内含子3远端区域常见的、相反构型的单倍型均预示着风险。我们现已在331名平原印第安男性和女性以及461名芬兰白人男性中重复了GABRA2与酒精中毒的关联研究。使用焦虑的维度测量指标——回避伤害（HA），我们还发现与酒精中毒的关联是由焦虑介导或调节的。对9个单核苷酸多态性（SNP）进行基因分型，发现了两个单倍型块。在之前涉及的块2区域内，我们确定了两种常见的、相反构型的风险单倍型，A和B。它们在芬兰人和平原印第安人中的频率有显著差异。在这两个人群中，大多数块2 SNP与酒精中毒显著相关。这种关联是由于酒精中毒者中两种纯合子的频率增加，这表明存在基因型相反的酒精中毒亚型的可能性。同样，没有显著的单倍型关联。以HA作为焦虑的指示变量，我们在两个人群中均发现单倍型与高维度和低维度焦虑的酒精中毒以及HA本身存在连锁关系。高HA酒精中毒者中较丰富单倍型（芬兰人为A，平原印第安人为B）的频率最高；低HA酒精中毒者中较不丰富单倍型（芬兰人为B，平原印第安人为A）的频率最高（芬兰人：P = 0.007，比值比[OR] = 2.1；平原印第安人：P = 0.040，OR = 1.9）。非酒精中毒者的频率处于中间水平。我们的结果表明，在GABRA2远端区域内存在一个或多个功能位点，这些位点在不同人群中可能不同，但通过焦虑的介导作用改变酒精中毒风险。
