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

描述(由申请人提供)：拟议项目的全球目标是识别和了解非裔美国人中酒精依赖、尼古丁依赖和其他药物依赖的遗传决定因素。到目前为止，大多数与成瘾有关的基因发现主要来自欧洲血统的样本。随着酒精依赖和相关疾病的全基因组关联研究(GWAS)涌现出大量数据，跨人群的复制和验证将在巩固关于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GWAS主要是在欧洲血统的样本中进行的，因此它们的结果将需要在人群中进行验证。跨种群验证是基因发现过程的一个关键方面，因为不同种族群体的等位基因频率不同。此外，非洲裔美国人和欧洲裔美国人样本之间的连锁不平衡模式的差异可以用来提炼最初在欧洲血统人群中发现的遗传信号。因此，该样本将有助于验证和完善基因发现的重要步骤。该项目将从非洲裔美国人社区确定1000个病例和1000个对照，这些病例和对照在性别、年龄、邮政编码和教育方面匹配。病例将包括寻求酒精依赖治疗的受试者，要么单独接受治疗，要么与其他药物依赖并存；对照组将包括曾饮酒但不依赖酒精或其他物质的受试者。男性和女性在病例和对照中的比例将均等，从而获得最大的权力来发现特定性别的关联。将通过广泛使用的高可靠性和既定效度的诊断性访谈，对酒精依赖、并存的药物依赖、精神障碍和危险因素进行彻底的评估。在欧洲或欧洲裔美国人的样本中发表的协会研究中的基因，以及在以白人为主的样本中出现的GWAS的发现，将在这个非裔美国人样本中测试与酒精依赖的关联。阳性结果将通过测试与其他物质依赖、共病精神障碍以及与一般成瘾倾向和外化行为相关的表型来进一步提炼。这些分析将确定以前的物质依赖关联发现是否适用于非裔美国人，以及是否在候选基因区域观察到与其他人群特定变异的关联。将使用最先进的方法确保候选基因区域的彻底覆盖，并将使用基因组控制SNPs来测试潜在的种群分层。总而言之，该项目将是第一批专门针对非裔美国人的酒精依赖基因研究之一，从而解决研究不足、服务不足的人群中的一个重大公共卫生问题。

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.