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确定和了解非洲裔美国人酒精依赖、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（GWAS）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遗传决定因素的知识方面发挥关键作用。由于这些新兴的GWAS主要是在欧洲血统的样本中进行的，因此他们的发现需要在人群中进行验证。交叉群体验证是基因发现过程的一个关键方面，因为等位基因频率在不同种族群体之间存在差异。此外，非洲裔美国人和欧洲裔美国人样本之间的联系不平衡模式的差异可用于改进最初在欧洲血统人群中识别的遗传信号。因此，该样本将有助于验证和完善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1,000例病例和1,000例对照病例，这些病例在性别、年龄、邮政编码和教育程度上相匹配。病例将包括寻求酒精依赖治疗的受试者，无论是单独的，还是与其他药物依赖共病的;对照将包括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组中的代表性相同，因此获得了检测性别特异性关联的最大能力。酒精依赖，共病药物依赖，精神疾病和风险因素的全面评估将进行广泛使用，诊断访谈具有高可靠性和既定的有效性。将对来自欧洲或欧美血统样本中已发表的相关研究的基因以及来自主要为白色样本中新兴GWAS的发现进行检测，以确定其与该非裔美国人样本中酒精依赖的相关性。阳性结果将通过检测与其他物质依赖、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相关性来进一步完善。这些分析将允许确定是否以前的关联结果的物质依赖是可推广到非洲裔美国人的人口，以及是否与其他人群特异性变异的候选基因区域中观察到的关联。将使用最先进的方法来确保候选基因区域的完全覆盖，并且将使用基因组对照SNP来测试潜在的群体分层。总之，该项目将是第一个专门针对非裔美国人的酒精依赖遗传研究项目，从而解决了一个研究不足和服务不足的人口中的重大公共卫生问题。公共卫生相关性：据估计，与酗酒相关的经济成本每年为1840亿美元，过度饮酒是当今美国可预防的早期死亡率的主要贡献者之一。虽然遗传学研究对酒精依赖等复杂疾病的个体化治疗和诊断的发展有很大的希望，但专门针对非裔美国人的酒精依赖遗传学研究相对较少。为了帮助确保这一人群实现遗传医学的益处，目前的申请寻求开发有酒精依赖和无酒精依赖的非裔美国人样本，用于有针对性的遗传研究，使用来自欧洲血统样本的发现来指导初步的遗传分析。

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.