Identifying Methamphetamine Risk Variants by Extreme Phenotype Exome Sequencing

 描述（由申请人提供）：甲基苯丙胺依赖（MD）是一个巨大的破坏性公共卫生问题，在世界范围内激增，包括美国和亚洲的许多地区。泰国是研究甲基苯丙胺依赖（MD）遗传学的最佳地点，因为与美国相比，泰国的遗传和环境异质性降低，并且在泰国流行病肆虐的背景下，研究成本较低。主要研究人员（R。Malison和J. Gelernter）已经建立了国际关系，并建立了必要的后勤基础设施，用于在泰国进行药物依赖性的人类遗传学研究，包括医学博士。利用曼谷现已建立的有效合作（Thanyarak研究所和朱拉隆功大学），我们已经收集了初步数据，以支持该项目的主要具体目标的可行性：1）收集和表型表征适合于MD的极端表型研究的临床样品，包括1000例严重受影响的MD病例（符合7/7 DSM-IV MD诊断标准）和1000名暴露于甲基苯丙胺但未受影响的对照组（符合7项MD标准中不超过1项的个人）; 2）使用全外显子组测序（WES）和GWAS来鉴定这种极端表型样本中的罕见和常见变体，然后确认其他先前收集的安非他明中排名最高的发现。来自美国（由我们的合作者Cindy Ehlers博士收集）和冰岛（由我们的合作者Thorgeir Thorgeirsson博士收集）的依赖队列;并在我们的欧洲和非洲裔美国可卡因依赖受试者样本中探索它们。我们还将使用相同的方法探索选择和反应冲动的遗传风险因素，与MD风险相关的遗传内表型。如果获得资助，目前的研究将是迄今为止第一个WES和/或GWAS MD研究。因此，目前的研究结果有可能大大提高我们对MD遗传风险因素的理解。这些即时的信息将导致对MD神经生物学的更好理解，并最终改善其诊断，治疗和预防的方法。

 DESCRIPTION (provided by applicant): Methamphetamine dependence (MD) is a hugely destructive public health problem that is surging worldwide, including in many parts of the US and Asia. Thailand is an optimal site for studying the genetics of methamphetamine dependence (MD), owing to decreased genetic and environmental heterogeneity compared to the US, and lower research costs, in the context of a devastating and widespread Thai epidemic. The Principal Investigators (R. Malison & J. Gelernter) have formed international relationships and established logistical infrastructures necessary for human genetic studies of drug dependence, including MD, in Thailand. Leveraging now-established and effective collaborations in Bangkok (Thanyarak Institute and Chulalongkorn University), we have collected preliminary data in support of the feasibility of the project's primary specific aims: 1)To collect and phenotypically characterize a clinical sample suitable for extreme phenotypic studies of MD, including 1000 severely affected MD cases (meeting 7/7 DSM-IV diagnostic criteria for MD) and 1000 methamphetamine exposed, but unaffected, controls (individuals meeting no more than 1 of 7 MD criteria); 2) Use whole exome sequencing (WES) and GWAS to identify both rare and common variants in this extreme phenotype sample and then confirm highest-ranked findings in other previously-collected amphetamine-dependent cohorts from the U.S. (collected by our collaborator Dr. Cindy Ehlers) and Iceland (collected by our collaborator Dr. Thorgeir Thorgeirsson); and explore them also in our European- and African-American sample of cocaine dependent subjects. We will also explore, using the same methods, genetic risk factors for choice and response impulsivity, heritable endophenotypes of relevance to MD risk. If funded, the current study would be the first WES and/or GWAS study of MD to date. Thus, results from the current study have the potential to advance dramatically our understanding of genetic risk factors for MD. Such immediate-term information will lead to an improved understanding of the neurobiology of MD and, ultimately, improved approaches to its diagnosis, treatment, and prevention.