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

说明(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；(2)帮助确定因果变异的跨人群对比图；(3)在独立样本中进行复制分析，以确定非裔美国人和高加索人大样本中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对注射吸毒者(IDU)中艾滋病毒-1感染的全球数据分析(DA026141)，并将城市健康研究(UHS)的3,878例非裔美国人和2,685名高加索人海洛因滥用病例与公开数据中的对照进行匹配。R21阶段侧重于识别、获得和匹配最优控制对象与案例。R33阶段侧重于对得出的病例/对照数据进行遗传分析。GWAs在识别导致包括药物滥用在内的复杂疾病风险的遗传变异(例如，尼古丁依赖的CHRNA5)方面取得了一些可复制的成功。很少有药物滥用的GWA，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，一些分子遗传学研究也得出了耐人寻味的结果，但没有任何基因变异有力地复制了导致这种遗传风险的证据。为了满足这一需要，我们将实现以下R21和R33目标：目标1：识别、评估和获取对照样本，以与全球海洛因滥用案例相匹配。目的2：从UHS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：评估非裔美国人和高加索人中海洛因滥用与UHS病例(n=6,563)和衍生对照的遗传相关性。目的4：对GWA的最高发现进行跨群体对比图谱，以筛选单核苷酸多态(SNPs)用于随访。目标5：在独立队列中复制主要研究结果。将6,563个海洛因滥用案例与资料库控制相匹配，拟议的Gwas将比任何海洛因滥用的基因研究大许多倍，也是所有药物滥用表型中最大的之一，允许检测预期的小到适度的遗传影响。因此，这项研究很可能发现并完善与海洛因滥用有关的遗传变异，为成瘾的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。 与公共健康相关：200多万美国人滥用海洛因，付出了巨大的个人和社会代价。约50%的海洛因滥用风险可归因于遗传因素。这项研究将确定高加索人和非裔美国人中与海洛因滥用有关的基因，并将大大有助于解决少数族裔在遗传研究中代表性不足的问题。这项研究的结果可能确定成瘾的重要生物学途径和开发新疗法的目标。

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.