Genetics of Alcohol Dependence in American Populations

描述（由申请人提供）：遗传因素有助于酒精依赖（AD）的发展。在识别特定风险基因方面已经取得了实质性进展，但目前已知的支持性位点仍然只占整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受试者和亲属，对非裔美国人（AAs）进行了过采样;我们还通过AD和相关表型的候选基因研究以及涉及AD风险的基因与环境相互作用（目前正在进行混合连锁不平衡研究）对AD风险的理解做出了贡献。全基因组关联研究（WGAS）具有揭示更多风险位点的潜力。这些研究的质量总是受到可用表型评估质量的限制;我们对最先进的表型表征的投资导致了一个样本，该样本应该是通过这种方法探测新风险基因座的杰出样本。在今次的申请中，我们建议增聘1250名副学士（主要是AA和EA）;并进行WGAS研究的2000欧洲美国AD主题和4000控制在两个波1000 affected和2000对照;以及相关基因座的后续研究（在已经收集的AD受试者的扩大样本和德国AD受影响者和对照的大样本中）通过SNP基因分型和深度测序。此外，我们将研究AD受试者子样本中的高分辨率拷贝数变异（CNV）。当研究的两波都完成时，我们将能够研究样品中的亚表型（例如，家族史阳性与阴性，AD伴或不伴其他物质依赖合并症），两者均在仅病例比较和与对照受试者比较中进行。已收集AA样本的配套WGAS应用程序已获得CIDR的临时批准，用于基因分型。当前的项目可以提供对AA和EA人群之间的风险位点进行指导性比较的机会，并有可能隔离相关区域。这个项目有可能大大有助于我们不断增长的知识遗传风险因素的AD和相关性状。

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.