Genome-Wide Association Study of Heroin Abuse: A Multiethnic Study

海洛因滥用的全基因组关联研究：一项多种族研究

基本信息

批准号：
8325514
负责人：
Eric Otto Johnson
金额：
$ 39.28万
依托单位：
RESEARCH TRIANGLE INSTITUTE
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：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8325514
关键词：
Accounting Address Admixture Adult Affect African American Age American Australia Biological Biology Candidate Disease Gene Case Study Caucasians Caucasoid Race Chinese People Clinical Cohort Studies Complex Confidential Information Conflict (Psychology)Controlled Study DRD2 gene DRD4 gene DSM-IV Data Data Analyses Data Set Dependence Detection Development Disease Dopamine Receptor Drug Controls Drug abuse Drug usage Ensure Environment Epidemiological Factors Ethnic Origin Ethnic group Evaluation Foundations Genes Genetic Genetic Determinism Genetic Heterogeneity Genetic Research Genetic Risk Genomics Genotype Goals Grant HIV HIV-1 Health Heroin Heroin Abuse Human Individual Infection Information Networks Injecting drug user Injection of therapeutic agent Instruction Letters Linkage Disequilibrium Maps Measures Metadata Methods Minority Molecular Genetics National Human Genome Research Institute National Institute of Drug Abuse Nicotine Dependence Non-Insulin-Dependent Diabetes Mellitus North America Opiate Addiction Opioid Participant Pathway interactions Persons Pharmacogenetics Phase Phenotype Policies Population Procedures Publishing Race Receptor Gene Recruitment Activity Reporting Research Research Personnel Resources Risk Running Sample Size Sampling Sampling Studies Scanning Severities Single Nucleotide Polymorphism Site Societies Source Substance abuse problem Surveys TCF7L2 gene Testing Time United States National Institutes of Health Urban Health Variant Work abstracting addiction base case control caucasian American cohort cost data sharing database of Genotypes and Phenotypes expectation follow-up genetic analysis genetic association genetic variant genome wide association study genome-wide linkage high risk interest meetings opioid abuse repository response success tool

项目摘要

PROJECT SUMMARY/ABSTRACT DESCRIPTION: See instructions. This must contain a summary of the proposed activity suitable for dissemination to the public (no proprietary/confidential information). It should be a self-contained description of the project and contain a statement of objectives and methods to be employed. It should be informative to other persons working in the same or related fields. DO NOT EXCEED THE SPACE PROVIDED. The overarching goal of this project is to identify and characterize genetic determinants of heroin abuse in large samples of African Americans and Caucasians by conducting (1) a case/control genome-wide association study (GWAS) of heroin abuse; (2) cross-population contrast mapping to help identify causal variants; and (3) replication analyses in independent samples. To achieve this goal we propose to capitalize on our current GWAS of HIV-1 infection among injection drug users (IDUs) (DA026141), and match the Urban Health Study's (UHS) 3,878 African American and 2,685 Caucasian heroin abuse cases to controls from publicly available data. The R21 phase focuses on identifying, obtaining, and matching optimal control subjects to cases. The R33 phase focuses on the genetic analyses of the derived case/control data. GWAS have had a number of replicable successes identifying genetic variants that contribute to the risk for complex diseases including for substance abuse (e.g., CHRNA5 with nicotine dependence). There are few GWAS of substance abuse, particularly for rarer high-risk substance abuse like heroin abuse. Although about 50% of the risk for heroin abuse is attributable to genetic factors and a number of molecular genetic studies have yielded intriguing results, no genetic variants have strongly replicated evidence of contributing to this genetic risk. To address this need, we will pursue the following R21 and R33 aims: Aim 1: To identify, evaluate, and acquire control samples to match to UHS heroin abuse cases for a GWAS. Aim 2: To develop analytic datasets from UHS heroin abuse cases and identified control samples. Aim 3: To evaluate genetic associations for heroin abuse in UHS cases (n=6,563) and derived controls among African Americans and Caucasians. Aim 4: To conduct cross-population contrast mapping of top GWA findings to select single-nucleotide polymorphisms (SNPs) for follow-up. Aim 5: To replicate primary findings in independent cohorts. Matching the 6,563 heroin abuse cases to repository controls, the proposed GWAS will be many times larger than any genetic study of heroin abuse and one of the largest of any drug abuse phenotype, allowing for detection of expected small to modest genetic effects. Thus, this GWAS is likely to discover, and to refine understanding of, genetic variants associated with heroin abuse, provide important clues to the biology of addiction, and indicate targets for further study and development of pharmacogenetic treatments.

项目概要/摘要描述：参见说明。这必须包含适合向公众传播的拟议活动的摘要（无专有/机密信息）。它应该是项目的独立描述，并包含目标和方法的陈述受雇。它应该为在相同或相关领域工作的其他人提供信息。请勿超出所提供的空间。该项目的总体目标是识别和描述海洛因滥用的遗传决定因素通过在非裔美国人和白种人的大样本中进行（1）病例/对照全基因组研究海洛因滥用关联研究（GWAS）； (2) 跨人群对比图帮助识别因果关系变体； (3) 独立样本的重复分析。为了实现这一目标，我们建议利用我们目前注射吸毒者 (IDU) 中 HIV-1 感染的 GWAS (DA026141)，并匹配城市健康研究 (UHS) 控制了 3,878 名非裔美国人和 2,685 名白人海洛因滥用案件来自公开数据。 R21阶段重点是识别、获取和匹配最优控制以案件为准。 R33 阶段侧重于对衍生病例/对照数据进行遗传分析。 GWAS 已经取得了许多可复制的成功，识别出导致风险的遗传变异用于复杂疾病，包括药物滥用（例如具有尼古丁依赖性的 CHRNA5）。有药物滥用的 GWAS 很少，特别是对于海洛因滥用等罕见的高风险药物滥用。虽然大约 50% 的海洛因滥用风险可归因于遗传因素和一些分子遗传因素研究已经取得了有趣的结果，没有任何遗传变异能够有力地重复证据对于这种遗传风险。为了满足这一需求，我们将追求以下 R21 和 R33 目标：目标 1：识别、评估和获取对照样本，以与 GWAS 的 UHS 海洛因滥用案例相匹配。目标 2：根据 UHS 海洛因滥用案例和确定的对照样本开发分析数据集。目标 3：评估 UHS 病例 (n=6,563) 和派生对照中海洛因滥用的遗传关联在非裔美国人和白种人中。目标 4：对顶级 GWA 研究结果进行跨群体对比作图，以选择单核苷酸多态性（SNP）用于后续研究。目标 5：在独立队列中复制主要发现。将 6,563 个海洛因滥用案例与存储库控制相匹配，拟议的 GWAS 将是许多倍比任何海洛因滥用的基因研究都要大，也是任何药物滥用表型中最大的研究之一，允许用于检测预期的小到中等的遗传效应。因此，这个 GWAS 很可能会发现并完善了解与海洛因滥用相关的遗传变异，为了解海洛因滥用的生物学提供了重要线索成瘾，并指出进一步研究和开发药物遗传学治疗的目标。