Controls for Association Studies of Alcoholism

描述（由申请人提供）： 酒精中毒是一个重要的公共卫生问题，因为它的流行和高发病率的病人和高影响他们的亲属。乙醇脱氢酶（ADH）基因簇和乙醇脱氢酶2基因座。已知ALDH 2影响某些人群（主要是东亚血统的人群）的酒精代谢和对酒精中毒的遗传易感性。我们对ADH基因簇的新的单倍型分析显示了显着的连锁不平衡，并将中国样本中酒精中毒的影响归因于仅一种单倍型。其他人最近的工作类似地在ALDH 2基因座发现了一个相关的单倍型。其他数据表明，在这些基因座尚未确定的等位基因可能与亚洲和其他人群中的酒精中毒和/或酒精代谢有关。考虑到全球人类遗传多样性的复杂性（部分来自以前的工作），这些数据支持在ADH基因簇和ALDH 2位点进行全面的全球遗传变异调查。因此，我们建议将单倍型的研究扩展到整个区域，通过鉴定涵盖整个区域的多态性，每个基因覆盖在分子短距离内，并在至少38个实验室人群样本中确定最具信息性的标记， 世界上所有的主要地区。将类似地研究包含ALDH 2的已知和新标记物的组合。中国、印度和非洲的合作者将继续帮助提高ADH和ALDH 2单倍型在各自地区人群中的覆盖率。对其他高等灵长类动物（黑猩猩、大猩猩、猩猩）的研究，以确定每个人类多态性的突变方向，将阐明现有变异的进化起源。我们将继续与其他研究人员合作，在三组不同的酒精中毒个体（一名中国人，一名德国人和一名澳大利亚人（北方欧洲血统））中检查这些单倍型，并将我们的多态性和单倍型数据传达给从事COGA和NIAAA酒精中毒连锁研究的合作者。因此，这个复杂和多方面的项目将提供必要的人口遗传基础，进一步研究ADH和ALDH 2基因座与酗酒，并将进行不同的应用，酗酒和酒精代谢的单倍型方法。这些研究将揭示不同遗传变异对酒精中毒的重要性，以及哪些单倍型可能具有隐蔽但功能相关的变异。

DESCRIPTION (provided by applicant): Alcoholism is a significant public health problem because of its prevalence and the high morbidity to patients and high impact on their relatives. The alcohol dehydrogenase (ADH) cluster of genes and the aldehydedehydrogenase 2 locus. (ALDH2) are known to affect alcohol metabolism and the genetic susceptibility to alcoholism in some populations, primarily populations of East Asian ancestry. Our new haplotype analyses of the ADH gene cluster show significant linkage disequilibrium and attribute the effect on alcoholism in the Chinese sample analyzed to only one haplotype. Recent work by others similarly finds a single relevant haplotype at the ALDH2 locus. Other data suggest that alleles not yet identified at these loci may be relevant to alcoholism and/or alcohol metabolism in Asian and other populations. Considered with the realization of the complexity of global human genetic diversity (developed in part from previous work on this grant), these data support undertaking a comprehensive global survey of genetic variation at the ADH gene cluster and at the ALDH2 locus. Therefore we propose to extend the study of the haplotypes across these entire regions, by identifying polymorphisms encompassing the entire region with each gene covered at molecularly short distances and type the most informative markers on at least 38 in-lab population samples representing all major parts of the world. A combination of known and new makers encompassing ALDH2 will similarly be studied. Collaborators in China, India, and Africa will continue to help develop better coverage of populations in their regions for ADH and ALDH2 haplotypes. Studies of other higher primates (chimpanzees, gorillas, orangutans) to determine the direction of mutation for each human polymorphism will illuminate the evolutionary origins of the existing variation. We will continue to collaborate with other researchers to examine these haplotypes in three different sets of individuals with alcoholism, one Chinese, one German, and one Australian (Northern European ancestry) and communicate our polymorphism and haplotype data to collaborators working on the COGA and NIAAA linkage studies of alcoholism. Thus, this complex and multifaceted project will provide the necessary population genetic basis for further studies of the ADH and ALDH2 loci as related to alcoholism and will undertake different applications to alcoholism and alcohol metabolism using haplotype approaches. Indications of the importance to alcoholism of different genetic variants and of which haplotypes may harbor cryptic but functionally relevant variation will result from these studies.