Genetics of Alcohol Dependence in African-Americans

描述（由申请人提供）：在所有受基因影响的特征中，酒精依赖（AD）是对美国乃至全世界的社会代价最高的特征之一。遗传流行病学研究一致报道AD的遗传率为~0.50-0.60。来自不同研究小组的全基因组连锁研究很少报道达到传统统计显著性的连锁峰，但有几个这样的峰在许多研究中被独立复制，支持其可能的有效性；在一些情况下，基于连锁结果的候选基因在不同的研究小组（包括我们的研究小组）中得到了强烈而一致的复制。尽管AD在社会上广泛存在，但少数群体，特别是非洲裔美国人（AAs），尚未得到充分研究。为了解决这个问题，我们在2002年启动了一个项目（AA11330），其中一个目标是收集AA酒精依赖病例和对照样本（通过混合连锁不平衡和其他基因定位方法进行定位）。我们现在总共招募了1500名无关的AA受试者，所有人都用最先进的SSADDA（药物依赖和酒精中毒半结构化评估）进行了评估，其中包括除了诊断标准之外的关于AD的大量细节。我们将从NIMH遗传学计划中增加额外的受试者来增加我们的ssadda评估的对照样本，产生1500例AD病例和1500例对照样本。基于一个较小的样本（1000/1000），我们之前通过CIDR提出了一个全基因组关联研究，使用Illumina HumanHap650Y标记集，该标记集被批准用于基因分型，并有可能获得额外的nih支持的独立项目的资助。该项核可已扩大，以适应目前订正的提议。这将是AA广告人群中开创性的WGAS；我们期望对AA群体的AD和AA群体的结构获得宝贵的新见解；并将讨论相关的表型，包括共病性疾病（如可卡因或阿片类药物依赖）。我们建议在额外的AA和EA样本中复制最显著的信号；并额外收集1250名经ssadda评估的受影响受试者，以便在2005年实施更强大的GWAS。

DESCRIPTION (provided by applicant): Alcohol dependence (AD), of all genetically influenced traits, is one of the most costly to society, in the United States and worldwide. Genetic epidemiologic studies consistently report the heritability of AD to be ~0.50-0.60. Genomewide linkage studies from different research groups have only rarely reported linkage peaks that attain conventional statistical significance, but several such peaks have been replicated independently in numerous studies, supporting their probable validity; and candidate genes based on linkage results have in several cases been replicated strongly and consistently across different research groups (including ours). Although AD cuts across society, minority populations, and specifically African-Americans (AAs), are understudied. To address this issue, we started a project in 2002 (AA11330) of which one goal was the collection of a sample of AA alcohol-dependent cases and controls (for mapping by admixture linkage disequilibrium, and other gene mapping methods). We have now recruited a total of 1500 unrelated AA subjects, all of whom were assessed with the state-of-the-art SSADDA (Semi-Structured Assessment for Drug Dependence and Alcoholism), which includes considerable detail regarding AD beyond merely the diagnostic criteria. We will augment our SSADDA-assessed control sample with additional subjects from the NIMH Genetics Initiative, yielding a sample of 1500 AD cases and 1500 controls. Based on a smaller sample (1000/1000), we previously proposed a genomewide association study through CIDR, using the Illumina HumanHap650Y marker set, which was approved for genotyping with the contingency that an additional independent NIH-supported project be funded. That approval has been extended to accommodate the present amended proposal. This would be a pioneering WGAS in an AA AD population; we expect to obtain invaluable new insights into AD in the AA population, and into the structure of the AA population; and will also address associated phenotypes, including comorbid disorders (such as cocaine or opioid dependence). We propose replication of most-significant signals in additional AA and EA samples; and collection of an additional 1250 SSADDA-assessed affected subjects to permit a more powerful GWAS in YR05. PUBLIC HEALTH RELEVANCE: Alcohol dependence is genetically influenced. The purpose of this project is to use a new and powerful technique, genomewide association analysis, to identify genes that influence risk for alcohol dependence in African-Americans, and to replicate key findings. Successful completion of this research would be expected to increase our understanding of alcohol dependence, and potentially to lead to early identification of susceptible individuals, and to new treatments.