A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity
A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity
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DOI：
10.1086/341290
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发表时间：
2002-07-01
影响因子：
9.8
通讯作者：
Kidd, KK
中科院分区：
文献类型：
--
作者：
Osier, MV;Pakstis, AJ;Kidd, KK
不同I类乙醇脱氢酶（ADH）基因的变体已被证明与防止酒精中毒的作用有关。我们实验室以前的工作表明，显示关联的两个位点处于连锁不平衡状态，并已确定ADH 1B Arg 47 His位点为致病位点，而ADH 1C Ile 349 Val位点仅因不平衡而显示关联。在这里，我们描述了一个初步研究的性质，连锁不平衡和遗传变异，在人口样本来自世界不同地区，在一个较大的部分ADH集群（包括三个I类ADH基因和ADH 7）。在我们研究的所有人群样本中，I类ADH簇中40 kb左右的连锁不平衡是中度到强烈的。我们观察到名义上显着的成对连锁不平衡，在某些人群中，ADH 7网站和一些I类ADH网站之间，在中等值和分子距离高达100 kb。我们的数据表明：（1）大多数ADH-酒精中毒相关性研究未能考虑ADH簇中可能含有病因学显著等位基因的许多位点;（2）各种ADH位点的相关性将取决于人群。I类ADH簇中的一些个体位点显示的值在F-st中是在同一人群子集中研究的几十个未连接位点中最高的。高值可归因于东亚的特定等位基因相对于世界其他地区的Fst的不一致频率。这些等位基因是仅在东亚样本中以高频率（>65%）存在的单一单倍型的一部分。这似乎不太可能，这是罕见的或未观察到的单倍型，在其他人群中，达到如此高的频率，因为随机遗传漂变单独。
Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across similar to40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show values that are among F-st the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those Fst in other regions of the world. These alleles are part of a single haplotype that exists at high (>65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone.