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：
7761906
负责人：
Eric Otto Johnson
金额：
$ 35.2万
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 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7761906
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 Classification Clinical Cohort Studies Complex Conflict (Psychology)Controlled Study 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 Letters Linkage Disequilibrium Maps Measures Metadata 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 Receptor Participant Pathway interactions 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 addiction base case control 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 public health relevance repository response success tool

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Over two million Americans abuse heroin, at great personal and societal cost. About 50% of the risk for heroin abuse is attributable to genetic factors. This study will identify genes associated with heroin abuse among Caucasian and African Americans and will contribute significantly to addressing minority under-representation in genetic research. The results of this study may identify important biological pathways for addiction and targets for developing new treatments.

描述（由申请人提供）：该项目的总体目标是通过进行 (1) 海洛因病例/对照全基因组关联研究 (GWAS)，在非裔美国人和白种人的大样本中识别和表征海洛因滥用的遗传决定因素虐待; (2) 跨人群对比映射，帮助识别因果变异； (3) 独立样本的重复分析。为了实现这一目标，我们建议利用目前注射吸毒者 (IDU) 中 HIV-1 感染的 GWAS (DA026141)，并将城市健康研究 (UHS) 的 3,878 名非裔美国人和 2,685 名白种人海洛因滥用案例与公共场所的对照进行匹配可用数据。 R21阶段的重点是识别、获取最优控制对象并将其与案例进行匹配。 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，识别出导致复杂疾病风险的遗传变异，包括药物滥用（例如，具有尼古丁依赖性的 CHRNA5）。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。尽管大约 50% 的海洛因滥用风险可归因于遗传因素，并且许多分子遗传学研究已经取得了有趣的结果，但没有任何遗传变异能够有力地重复证据证明导致这种遗传风险。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) 中海洛因滥用的遗传关联以及非裔美国人和白种人中的衍生对照。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) 进行后续研究。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储存库对照相匹配，拟议的 GWAS 将比任何海洛因滥用基因研究大很多倍，也是最大的药物滥用表型研究之一，从而可以检测预期的小到中等的遗传效应。因此，该 GWAS 可能会发现并加深对与海洛因滥用相关的遗传变异的理解，为成瘾生物学提供重要线索，并为进一步研究和开发药物遗传学治疗指明目标。公共卫生相关性：超过 200 万美国人滥用海洛因，造成巨大的个人和社会成本。大约 50% 的海洛因滥用风险可归因于遗传因素。这项研究将确定与白种人和非裔美国人滥用海洛因相关的基因，并将为解决基因研究中少数族裔代表性不足的问题做出重大贡献。这项研究的结果可能会确定成瘾的重要生物学途径和开发新疗法的目标。