Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism
Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism
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DOI：
10.1002/ajmg.b.30336
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发表时间：
2006-09-05
影响因子：
2.8
通讯作者：
Goldman, David
中科院分区：
文献类型：
--
作者：
Enoch, Mary-Anne;Schwartz, Lori;Goldman, David
GABAA（α 2）受体基因（GABRA 2）调节焦虑和应激反应。最近的三项相关研究表明GABRA 2与酒精中毒有关，然而在这些论文中，内含子3远端区域的两种常见的相反构型单倍型都预测了风险。我们现在已经在331名平原印第安男性和女性以及461名芬兰白人男性中复制了GABRA 2与酗酒的关联。使用维度测量焦虑，避免伤害（HA），我们还发现，与酗酒的关联是介导的，或缓和，焦虑。对9个SNP进行基因分型，揭示了2个单倍型块。在先前涉及的第2区，我们确定了两个常见的，相反的配置风险单倍型，A和B。它们的频率在芬兰人和平原印第安人中有显著差异。在这两个群体中，大多数第2区SNP与酗酒显著相关。这种关联是由于酗酒者中两种纯合子的频率增加，表明酗酒亚型可能具有相反的基因型。一致地，没有显著的单倍型关联。使用HA作为焦虑的指标变量，我们发现单倍型连锁酗酒与高，低维度焦虑，HA本身，在这两个人群中。高HA酗酒者具有最高频率的更丰富的单倍型（芬兰人A，平原印第安人B）;低HA酗酒者具有最高频率的不太丰富的单倍型（芬兰人B，平原印第安人A）（芬兰人：P = 0.007，OR = 2.1，平原印第安人：P = 0.040，OR = 0.9）。不酗酒的人有中间频率。我们的研究结果表明，在远端GABP，42区域是一个功能位点或位点，可能不同的人群之间，但改变酗酒的风险，通过调解行动的焦虑。(c)2006 Wiley-Liss，Inc.
The GABAA(alpha 2) receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite-onfiguration 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 = .9). Nonalcoholics had intermediate frequencies. Our results suggest that within the distal GABP,42 region is a functional locus or loci that may differ between populations but that alters risk for alcoholism via the mediating action of anxiety. (c) 2006 Wiley-Liss, Inc.