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

非裔美国人的酒精依赖：病例对照遗传学研究

• 批准号: 8248341
• 负责人: Richard A Grucza
• 金额: $ 66.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248341
• 关键词: Address; African American; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; American; Antisocial Personality Disorder; Blood specimen; Candidate Disease Gene; Code; Communities; Complex; Conduct Disorder; Data; Development; Diagnosis; Diagnostic; Disease; Drug Addiction; Drug Modulation; Education; Ensure; Ethanol Metabolism; Ethnic group; European; Evaluation; Exhibits; Family history of; Future; Gender; Gene Frequency; Gene Targeting; Generations; Genes; Genetic; Genetic Determinism; Genetic Medicine; Genetic Polymorphism; Genetic Research; Genomics; Genotype; Grant; Health; Hylobates Genus; IGA Glomerulonephritis; Individual; Interview; Knowledge; Light; Linkage Disequilibrium; Major Depressive Disorder; Marijuana; Measurement; Mediating; Mental disorders; Methods; Neurotransmitters; Nicotine Dependence; Pattern; Personality; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Play; Population; Process; Property; Public Health; Publishing; Race; Reporting; Research; Resources; Rewards; Risk; Risk Assessment; Risk Factors; Role; Sampling; Signal Transduction; Smoking; Specificity; Stratification; Structure; Substance Addiction; System; Taste Perception; Testing; Underserved Population; United States; Validation; Variant; Woman; addiction; base; case control; disorder risk; economic cost; ethnic difference; externalizing behavior; gene discovery; genetic analysis; genome wide association study; health disparity; men; mortality; novel; receptor; socioeconomics; stem; working group

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.

描述（由申请人提供）：拟议项目的全球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，大多数与成瘾相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）产生大量数据，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。由于这些新兴的 GWAS 主要是在欧洲血统样本中进行的，因此它们的研究结果需要在人群中进行验证。跨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中有所不同。此外，非洲裔美国人和欧洲裔美国人样本之间连锁不平衡模式的差异可用于细化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遗传发现的重要步骤。该项目将确定来自非裔美国人社区的 1,000 个病例和 1,000 个与性别、年龄、邮政编码和教育程度相匹配的对照。病例将包括寻求酒精依赖治疗的受试者，无论是单独治疗还是与其他药物依赖共存；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中将具有同等代表性，以便获得检测性别特异性关联的最大能力。将通过广泛使用的具有高可靠性和确定有效性的诊断访谈来对酒精依赖、共病药物依赖、精神疾病和危险因素进行全面评估。已发表的欧洲或欧美血统样本关联研究中的基因，以及主要白人样本中新兴 GWAS 的发现，将在该非裔美国人样本中测试与酒精依赖的关联。通过测试与其他物质依赖、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，将进一步完善积极的发现。这些分析将有助于确定先前的物质依赖性关联发现是否适用于非裔美国人群体，以及在候选基因区域中是否观察到与其他群体特异性变异的关联。最先进的方法将用于确保候选基因区域的彻底覆盖，并且基因组控制 SNP 将用于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学研究，从而解决研究不足和服务不足的人群中的重大公共卫生问题。公共卫生相关性：每年与酗酒相关的经济成本估计为 1,840 亿美元，过量饮酒是当今美国可预防的早期死亡的主要原因之一。尽管基因研究为酒精依赖等复杂疾病的个体化治疗和诊断带来了巨大希望，但专门针对非裔美国人的酒精依赖基因研究相对较少。为了帮助确保遗传医学对该人群的益处得以实现，当前的申请旨在开发一个有或没有酒精依赖的非裔美国人样本，用于有针对性的遗传研究，利用欧洲血统样本的发现来指导初始遗传研究。分析。