ALCOHOL DEPENDENCE IN AFRICAN AMERICANS: A CASE-CONTROL GENETIC STUDY

描述（由申请人提供）：拟议项目的总体目标是确定和了解非裔美国人酒精依赖、共病尼古丁依赖和其他药物依赖的遗传决定因素。迄今为止，大多数与成瘾有关的基因发现都来自主要是欧洲血统的样本。随着酒精依赖和相关疾病的全基因组关联研究（GWASs）中出现的大量数据，跨人群的复制和验证将在巩固有关这些疾病的遗传决定因素的知识方面发挥关键作用。由于这些新出现的GWASs主要是在欧洲血统的样本中进行的，因此它们的发现将需要在整个人群中得到验证。跨种群验证是基因发现过程的一个关键方面，因为等位基因的频率在不同的种族群体中存在差异。此外，非裔美国人和欧裔美国人样本之间联系不平衡模式的差异可以用来改进最初在欧洲血统人群中发现的遗传信号。因此，该样本将促进验证和改进遗传发现的重要步骤。该项目将确定来自非洲裔美国人社区的1000例病例和1000例对照，这些病例与性别、年龄、邮政编码和教育程度相匹配。病例将包括寻求酒精依赖治疗的受试者，单独或与其他药物依赖合并症；对照组包括饮用过酒精但不依赖酒精或其他物质的受试者。在病例和对照中，男性和女性的比例将是相等的，以便获得最大的权力来检测特定性别的关联。对酒精依赖、共病药物依赖、精神障碍和危险因素的全面评估将通过广泛使用的高信度和既定效度的诊断性访谈进行。来自已发表的欧洲或欧美血统样本关联研究的基因，以及来自以白人为主的样本中新出现的GWASs的发现，将被测试与非裔美国人样本中酒精依赖的关联。阳性结果将通过与其他物质依赖、共病精神疾病以及与一般成瘾倾向和外化行为相关的表型的关联测试进一步完善。这些分析将允许确定先前的物质依赖相关发现是否可推广到非裔美国人人群，以及是否在候选基因区域中观察到与其他人群特异性变异的关联。最先进的方法将用于确保候选基因区域的全面覆盖，基因组控制snp将用于测试潜在的群体分层。总之，这个项目将是第一个专门针对非裔美国人的酒精依赖基因研究，从而在研究不足和服务不足的人群中解决一个重大的公共卫生问题。公共卫生相关性：与酒精滥用相关的经济成本估计为每年1840亿美元，过度饮酒是当今美国可预防的早期死亡的主要原因之一。尽管基因研究对像酒精依赖这样的复杂疾病的个性化治疗和诊断有着巨大的希望，但相对而言，针对非裔美国人的酒精依赖的基因研究很少。为了确保基因医学的益处在这一人群中得以实现，目前的申请旨在开发一个有酒精依赖和没有酒精依赖的非裔美国人样本，用于有针对性的基因研究，使用来自欧洲血统样本的发现来指导最初的基因分析。

DESCRIPTION (provided by applicant): The global aim of the proposed project is to identify and understand the genetic determinants of alcohol dependence, comorbid nicotine dependence, and other drug dependence in African-Americans. To date, the majority of genetic findings related to addiction have come from samples of primarily European descent. With the large volume of data emerging from genome-wide association studies (GWASs) of alcohol dependence and related disorders, replication and validation across populations will play critical roles in solidifying knowledge about genetic determinants of these disorders. Because these emerging GWASs are largely being conducted primarily in samples of European descent, findings from them will need to be validated across populations. Cross-population validation is a key aspect of the gene-discovery process because allele frequencies differ across ethnic groups. In addition, differences in linkage-disequilibrium patterns between African-American and European-American samples can be used to refine genetic signals initially identified in populations of European descent. Hence, this sample would facilitate the important steps of validation and refinement of genetic findings. The project will ascertain 1,000 cases and 1,000 controls matched on gender, age, zip code, and education, from the African-American community. Cases will consist of subjects seeking treatment for alcohol dependence, either alone, or comorbid with other drug dependence; controls will comprise subjects who have consumed alcohol, but are not dependent on alcohol or other substances. Men and women will be equally represented among both cases and controls, so that maximal power to detect gender specific associations is obtained. Thorough assessment of alcohol dependence, comorbid drug dependence, psychiatric disorders, and risk factors will be carried out with widely-used, diagnostic interviews with high reliability and established validity. Genes from published association studies in samples of European or European-American descent, and findings from emerging GWASs in predominantly White samples will be tested for association with alcohol dependence in this African-American sample. Positive findings will be further refined by testing for association with other substance dependence, comorbid psychiatric disorders, and phenotypes related to general addiction liability and externalizing behavior. These analyses will allow determination of whether previous association findings for substance dependence are generalizable to the African-American population, and whether association with other population-specific variants is observed in the candidate gene regions. State-of-the art methods will be used to ensure thorough coverage of candidate gene regions, and genomic control SNPs will be used to test for potential population stratification. In summary, this project would be among the first genetic studies of alcohol dependence to focus specifically on African- Americans, thus addressing a significant public health problem in an under-studied and underserved population. PUBLIC HEALTH RELEVANCE: The economic costs associated with abuse of alcohol have been estimated at $184 billion per year and excessive alcohol use is one of the top contributors to preventable early mortality in the United States today. Though genetic research holds great promise toward the development of individualized treatment and diagnosis for complex disease such as alcohol dependence, there have been comparatively few genetic studies of alcohol dependence that have focused specifically on African-Americans. To help ensure that the benefits of genetic medicine are realized for this population, the current application seeks to develop a sample of African- Americans with and without alcohol dependence, for targeted genetic studies, using findings from samples of European-descent to guide initial genetic analyses.