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: 7809663
• 负责人: Richard A Grucza
• 金额: $ 66.39万
• 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/7809663
• 关键词: Address; African American; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; American; Antisocial Personality Disorder; Arts; Blood specimen; Candidate Disease Gene; Code; Communities; Complex; 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; 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; public health relevance; 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）：拟议项目的全球目的是识别和理解酒精依赖性，合并症尼古丁依赖性以及非裔美国人的其他药物依赖性的遗传决定因素。迄今为止，与成瘾有关的大多数遗传发现都来自主要是欧洲血统的样本。随着大量数据从全基因组关联研究（GWASS）的酒精依赖性和相关疾病中出现，跨种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GWASS主要是在欧洲血统的样本中进行的，因此需要在欧洲血统的样本中进行验证。跨种群验证是基因发现过程的关键方面，因为等位基因频率在各个族群之间有所不同。此外，非洲裔美国人和欧美样本之间的连锁区限制模式的差异可用于完善最初在欧洲血统种群中鉴定出的遗传信号。因此，该样本将促​​进遗传发现验证和完善的重要步骤。该项目将确定来自非裔美国人社区的性别，年龄，邮政编码和教育的1,000例和1,000个控件。病例将包括寻求对酒精依赖治疗的受试者，或与其他药物依赖性合并；控件将包括饮酒但不依赖酒精或其他物质的受试者。男人和女人将在病例和对照中同样代表，以便获得最大的能力来检测性别特定的关联。将通过广泛使用的，高可靠性和确定的有效性进行彻底评估酒精依赖，合并药物依赖，精神疾病和危险因素的评估。来自欧洲或欧美血统样本的已发表关联研究的基因，以及以白色样品为主的新兴GWASS的发现，将在该非裔美国人样本中测试与酒精依赖相关的基因。通过测试与其他物质依赖性，合并症的精神疾病以及与一般成瘾责任和外部化行为有关的表型，将进一步完善积极的发现。这些分析将允许确定早期的物质依赖性发现是否可以推广到非裔美国人人口，以及是否在候选基因区域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彻底覆盖候选基因区域，并将使用基因组控制SNP来测试潜在的人群分层。总而言之，该项目将是针对非裔美国人专门关注的酒精依赖遗传研究之一，从而解决了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：与滥用酒精有关的经济成本估计为每年1840亿美元，而过度使用酒精是今天美国可预防早期死亡率的主要贡献者之一。尽管遗传学研究在开发诸如酒精依赖等复杂疾病的个性化治疗和诊断方面具有巨大的希望，但对酒精依赖性的遗传研究相对较少，这些研究专门针对非裔美国人。为了帮助确保为该人群实现遗传医学的益处，目前的申请使用有针对性的遗传研究来开发具有或不含酒精依赖的非裔美国人样本，使用欧洲淡季样本来指导初始遗传分析。