Identifying Methamphetamine Risk Variants by Extreme Phenotype Exome Sequencing

 描述(申请人提供)：甲基苯丙胺依赖(MD)是一个极具破坏性的公共卫生问题，正在全球范围内激增，包括在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，这是因为与美国相比，泰国的遗传和环境异质性较低，而且在泰国毁灭性和大范围流行的背景下，研究成本较低。首席调查人员(R.Malison和J.Gelernter)已经建立了国际关系，并建立了泰国包括MD在内的药物依赖的人类基因研究所需的后勤基础设施。利用曼谷现已建立的有效合作(坦雅拉克研究所和朱拉隆功大学)，我们收集了初步数据，以支持该项目主要具体目标的可行性：1)收集适合MD极端表型研究的临床样本并进行表型分析，包括1000例严重感染的MD病例(符合7/7 DSM-IV诊断标准)和1000例暴露但未受影响的甲基苯丙胺对照组(符合7项MD标准中不超过1项的个人)；2)使用完整外显子组测序(WES)和GWAS来识别这个极端表型样本中的罕见和常见变异，然后确认在来自美国(由我们的合作者Cindy Ehler博士收集)和冰岛(由我们的合作者Thorgeir Thorgeirsson博士收集)的其他苯丙胺依赖队列中排名最高的发现；并在我们的欧洲和非洲裔美国人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，以及与MD风险相关的遗传内表型。如果得到资助，目前的研究将是迄今为止第一个关于MD的WES和/或GWAS研究。因此，目前的研究结果有可能极大地促进我们对MD的遗传风险因素的理解。这些即时信息将导致对MD神经生物学的更好理解，并最终改进其诊断、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.