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Genetics of Alcohol Dependence in American Populations

美国人酒精依赖的遗传学

基本信息

批准号：
8434888
负责人：
JOEL GELERNTER
金额：
$ 52.93万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434888
关键词：
Accounting Admixture Affect African American Alcohol dependence Alcohol withdrawal syndrome American Candidate Disease Gene Cocaine Dependence Collaborations Comorbidity Companions Copy Number Polymorphism Custom Data Development Diagnostic Early identification European Family Funding Genes Genetic Genetic Risk Genotype German population Germany Health Individual Interview Investments Knowledge Lead Linkage Disequilibrium Maps Methods National Institute of Drug Abuse Nicotine Dependence Oligonucleotide Microarrays Phenotype Population Psychiatry Publications Recording of previous events Recruitment Activity Relative (related person)Research Resolution Risk SNP genotyping Sampling Substance Addiction Techniques Universities Withdrawal Symptom base comparison group cost deep sequencing design disorder risk follow-up gene environment interaction genetic linkage genetic risk factor genome wide association study genome-wide indexing novel trait

项目摘要

DESCRIPTION (provided by applicant): Genetic factors contribute to the development of alcohol dependence (AD). Substantial progress has been made in identifying specific risk genes, but currently known well-supported loci still account for only a small proportion of the overall disease risk. In the last iteration of this project, we recruited and rigorously assessed ~2000 AD subjects and relatives, with oversampling of African Americans (AAs); we also contributed to the understanding of AD risk though candidate gene studies of AD and related phenotypes, and gene-by-environment interaction involving AD risk (with mapping by admixture linkage disequilibrium studies currently in progress). It is widely appreciated that whole genome association studies (WGAS) have the potential to reveal more risk loci. The quality of such studies is always limited by the quality of the available phenotypic assessments; our investment in state-of-the-art phenotypic characterization has resulted in a sample that should be an outstanding one to probe for novel risk loci by this method. In the present application, we propose to recruit an additional 1250 AD subjects (primarily AAs and EAs); and to conduct a WGAS study of 2000 European American AD subjects and 4000 controls in two waves of 1000 affecteds and 2000 controls; and follow-up studies of implicated loci (in an expanded sample of already-collected AD subjects and a large sample of German AD affecteds and controls) via SNP genotyping and deep sequencing. Additionally, we will study high resolution copy number variation (CNV) in a subsample of AD subjects. When both waves of the study have been completed, we will be able to study subphenotypes within the sample (e.g., family history positive vs. negative, AD with or without other substance dependence comorbidity), both in case-only comparisons and in comparison to control subjects. A companion WGAS application with already-collected AA samples has been contingently-approved by CIDR for genotyping. The current project could provide the opportunity for instructive comparison of risk loci between AA and EA populations, with the potential to isolate associated regions. This project has the potential to contribute substantially to our growing knowledge of genetic risk factors for AD and related traits.

描述（由申请人提供）：遗传因素导致酒精依赖（AD）的发展。在识别特定风险基因方面已经取得了实质性进展，但目前已知的得到充分支持的基因座仍然只占总体疾病风险的一小部分。在该项目的最后一次迭代中，我们招募并严格评估了约 2000 名 AD 受试者及其亲属，并对非裔美国人 (AA) 进行了过采样；我们还通过 AD 和相关表型的候选基因研究以及涉及 AD 风险的基因与环境相互作用（目前正在进行混合连锁不平衡研究进行绘图），为了解 AD 风险做出了贡献。人们普遍认为，全基因组关联研究（WGAS）有可能揭示更多的风险位点。此类研究的质量始终受到现有表型评估质量的限制；我们对最先进的表型表征的投资产生了一个样本，该样本应该是通过这种方法探索新风险位点的杰出样本。在本申请中，我们建议额外招募1250名AD受试者（主要是AA和EA）；对 2000 名欧洲裔美国 AD 受试者和 4000 名对照者进行 WGAS 研究，分两批 1000 名受影响者和 2000 名对照者；通过 SNP 基因分型和深度测序对相关位点进行后续研究（在已收集的 AD 受试者的扩大样本以及德国 AD 受影响者和对照的大量样本中）。此外，我们将研究 AD 受试者子样本中的高分辨率拷贝数变异 (CNV)。当两波研究完成后，我们将能够研究样本中的亚表型（例如，阳性家族史与阴性家族史、有或没有其他物质依赖合并症的 AD），无论是仅病例比较还是与对照受试者比较。 CIDR 已偶然批准了带有已收集的 AA 样本的配套 WGAS 应用程序用于基因分型。当前的项目可以为 AA 和 EA 群体之间的风险位点进行指导性比较提供机会，并有可能隔离相关区域。该项目有可能为我们不断加深对 AD 遗传风险因素和相关性状的了解做出重大贡献。