Genetics of Alcohol Dependence in American Populations

描述（由申请人提供）：遗传因素导致酒精依赖（AD）的发展。在确定特定风险基因方面已经取得了实质性进展，但目前已知的得到充分支持的基因座仍然只占总体疾病风险的一小部分。在该项目的最后一次迭代中，我们招募并严格评估了约2000名AD受试者及其亲属，并对非裔美国人（AAs）进行了过采样；我们还通过阿尔茨海默病的候选基因研究和相关表型，以及涉及阿尔茨海默病风险的基因-环境相互作用（目前正在进行的混合连锁不平衡研究），为了解阿尔茨海默病的风险做出了贡献。人们普遍认为，全基因组关联研究（WGAS）有可能揭示更多的风险位点。这类研究的质量总是受到可用表型评估质量的限制；我们在最先进的表型表征方面的投资已经产生了一个样本，应该是一个通过这种方法探索新的风险位点的杰出样本。在目前的申请中，我们建议再招募1250名AD受试者（主要是AAs和ea）；并对2000名欧美AD受试者和4000名对照者进行WGAS研究，分为两组，1000名受影响者和2000名对照者；并通过SNP基因分型和深度测序对相关位点进行后续研究（在已经收集的AD受试者和德国AD患者和对照组的扩大样本中）。此外，我们将在AD受试者的子样本中研究高分辨率拷贝数变化（CNV）。当两波研究完成后，我们将能够研究样本内的亚表型（例如，家族史阳性与阴性，AD伴或不伴其他物质依赖合并症），包括病例比较和与对照受试者的比较。已经收集的AA样本的WGAS配套应用已偶然获得CIDR的基因分型批准。目前的项目可以为AA和EA人群之间的风险位点的指标性比较提供机会，并有可能分离相关区域。这个项目有可能为我们对阿尔茨海默病和相关性状的遗传风险因素的不断增长的知识做出重大贡献。

DESCRIPTION (provided by applicant): Genetic factors contribute to the development of alcohol dependence (AD). Substantial progress has been made in identifying specific risk genes, but currently known well-supported loci still account for only a small proportion of the overall disease risk. In the last iteration of this project, we recruited and rigorously assessed ~2000 AD subjects and relatives, with oversampling of African Americans (AAs); we also contributed to the understanding of AD risk though candidate gene studies of AD and related phenotypes, and gene-by-environment interaction involving AD risk (with mapping by admixture linkage disequilibrium studies currently in progress). It is widely appreciated that whole genome association studies (WGAS) have the potential to reveal more risk loci. The quality of such studies is always limited by the quality of the available phenotypic assessments; our investment in state-of-the-art phenotypic characterization has resulted in a sample that should be an outstanding one to probe for novel risk loci by this method. In the present application, we propose to recruit an additional 1250 AD subjects (primarily AAs and EAs); and to conduct a WGAS study of 2000 European American AD subjects and 4000 controls in two waves of 1000 affecteds and 2000 controls; and follow-up studies of implicated loci (in an expanded sample of already-collected AD subjects and a large sample of German AD affecteds and controls) via SNP genotyping and deep sequencing. Additionally, we will study high resolution copy number variation (CNV) in a subsample of AD subjects. When both waves of the study have been completed, we will be able to study subphenotypes within the sample (e.g., family history positive vs. negative, AD with or without other substance dependence comorbidity), both in case-only comparisons and in comparison to control subjects. A companion WGAS application with already-collected AA samples has been contingently-approved by CIDR for genotyping. The current project could provide the opportunity for instructive comparison of risk loci between AA and EA populations, with the potential to isolate associated regions. This project has the potential to contribute substantially to our growing knowledge of genetic risk factors for AD and related traits.