Genetics of Alcohol Dependence in African-Americans

描述(申请人提供)：酒精依赖(AD)是所有受基因影响的特征之一，在美国和全世界都是最昂贵的社会之一。遗传流行病学研究一直报告阿尔茨海默病的遗传度为~0.50-0.60。来自不同研究组的全基因组连锁研究很少报告达到常规统计意义的连锁峰，但在许多研究中独立复制了几个这样的峰，支持其可能的有效性；在几个案例中，基于连锁结果的候选基因在不同的研究组(包括我们的研究组)中得到了强烈和一致的复制。尽管AD横跨整个社会，但少数群体，特别是非洲裔美国人(AA)，研究不足。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的样本(用于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，所有人都接受了最先进的SSADDA(药物依赖和酒精中毒的半结构化评估)的评估，其中包括除了诊断标准之外关于AD的相当多的细节。我们将用来自NIMH遗传学计划的额外受试者来扩充我们的SSADDA评估对照样本，产生1500例AD病例和1500名对照样本。基于较小的样本(1000/1000)，我们之前提出了通过CIDR进行全基因组关联研究，使用Illumina HumanHap650Y标记集，该标记集被批准用于基因分型，但意外情况下，需要额外资助一个由NIH支持的独立项目。这项批准已予延长，以配合目前经修订的建议。这将是AA AD人群中的一次开创性的WGA；我们希望对AA人群中的AD以及AA人群的结构获得宝贵的新见解；还将解决相关的表型，包括共病障碍(如可卡因或阿片依赖)。我们建议在额外的AA和EA样本中复制最显著的信号；并收集额外的1250个经SSADDA评估的受影响受试者，以允许在YR05中进行更强大的GWAS。 与公共健康相关：酒精依赖受基因影响。这个项目的目的是使用一种新的强大的技术-全基因组关联分析，来识别影响非裔美国人酒精依赖风险的基因，并复制关键发现。这项研究的成功完成将有望增加我们对酒精依赖的了解，并有可能导致早期识别易感人群，并找到新的治疗方法。

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.