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

描述（由申请人提供）：本项目的总体目标是通过进行(1)海洛因滥用的病例/对照全基因组关联研究（GWAS），在非洲裔美国人和白种人的大样本中确定和表征海洛因滥用的遗传决定因素；(2)跨种群对比图，帮助识别因果变异；(3)独立样本的复制分析。为了实现这一目标，我们建议利用我们目前注射吸毒者（IDUs）中HIV-1感染的GWAS (DA026141)，并将城市健康研究（UHS）的3,878名非洲裔美国人和2,685名白人海洛因滥用病例与公开可用数据的对照进行匹配。R21阶段的重点是识别、获取和匹配最优对照受试者。R33阶段侧重于衍生病例/对照数据的遗传分析。GWAS已经取得了一些可复制的成功，确定了导致复杂疾病风险的遗传变异，包括药物滥用风险（例如，尼古丁依赖的CHRNA5）。很少有药物滥用的GWAS，特别是对于像海洛因滥用这样罕见的高风险药物滥用。虽然海洛因滥用的风险中约有50%可归因于遗传因素，而且一些分子遗传学研究也取得了令人感兴趣的结果，但没有任何遗传变异能够有力地重复证明是造成这种遗传风险的原因。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UHS的海洛因滥用案例相匹配。目的2：从保健处海洛因滥用案例和确定的对照样本中开发分析数据集。目的3：评估非裔美国人和白种人中UHS病例（n= 6563）和衍生对照中海洛因滥用的遗传关联。目的4：对顶级GWA发现进行跨群体对比作图，以选择单核苷酸多态性（snp）进行随访。目的5：在独立队列中重复主要研究结果。将6,563个海洛因滥用案例与存储库对照相匹配，拟议的GWAS将比任何海洛因滥用的遗传研究都要大许多倍，并且是任何药物滥用表型中最大的研究之一，允许检测预期的小到中等的遗传影响。因此，该GWAS可能会发现并完善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治疗指明目标。

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.