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

描述（由申请人提供）：该项目的总体目标是通过进行（1）海洛因滥用的病例/对照全基因组关联研究（GWAS）;（2）交叉人群对比图，以帮助识别因果变异;（3）独立样本中的重复分析，在大样本非裔美国人和高加索人中识别和表征海洛因滥用的遗传决定因素。为了实现这一目标，我们建议利用我们目前在注射毒品使用者（IDUs）中HIV-1感染的GWAS（DA 026141），并将城市健康研究（UHS）的3，878例非洲裔美国人和2，685例白人海洛因滥用病例与公开数据的对照进行匹配。R21阶段的重点是识别，获得和匹配最佳控制对象的情况下。R33阶段侧重于对衍生病例/对照数据的遗传分析。GWAS已经取得了许多可复制的成功，确定了导致包括药物滥用在内的复杂疾病风险的遗传变异（例如，CHRNA 5与尼古丁依赖）。很少有药物滥用的GWAS，特别是像海洛因滥用这样罕见的高风险药物滥用。尽管约50%的海洛因滥用风险可归因于遗传因素，并且一些分子遗传学研究已经产生了有趣的结果，但没有遗传变异强烈复制了导致这种遗传风险的证据。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，以匹配UHS海洛因滥用案件的GWAS。目的2：从UHS海洛因滥用病例和确定的对照样本中开发分析数据集。目的3：评估UHS病例（n= 6，563）和非裔美国人和高加索人中海洛因滥用的遗传相关性。目的4：对GWA的主要发现进行跨人群对比映射，以选择单核苷酸多态性（SNP）进行随访。目的5：在独立队列中复制主要结果。将6，563例海洛因滥用病例与储存库对照相匹配，拟议的GWAS将比任何海洛因滥用遗传研究大很多倍，也是任何药物滥用表型中最大的一个，允许检测预期的小到适度的遗传效应。因此，这个GWAS可能会发现，并完善理解，与海洛因滥用相关的遗传变异，提供成瘾生物学的重要线索，并为进一步研究和药物遗传学治疗的发展指明目标。 公共卫生相关性：超过200万美国人滥用海洛因，付出了巨大的个人和社会代价。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人和非洲裔美国人滥用海洛因相关的基因，并将大大有助于解决遗传研究中少数民族代表性不足的问题。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治疗方法的目标。

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.