Identifying Methamphetamine Risk Variants by Extreme Phenotype Exome Sequencing

通过极端表型外显子组测序识别甲基苯丙胺风险变异体

• 批准号: 9280890
• 负责人: JOEL GELERNTER
• 金额: $ 72.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280890
• 关键词: Affect; African American; Alcoholism; Amphetamines; Asia; Asians; Chinese People; Clinical; Cocaine; Collaborations; Country; DNA; DSM-IV; Data; Diagnosis; Diagnostic; Disease; Drug Addiction; Drug abuse; Epidemic; European; Faculty; Failure; Funding; Future; Genes; Genetic; Genetic study; Heritability; Heterogeneity; Hospitals; Human Genetics; Iceland; Impulsivity; Individual; Institutes; International; Lead; Light; Logistics; Medicine; Methamphetamine; Methamphetamine dependence; Methods; Modernization; Neurobiology; Pathway interactions; Phenotype; Population; Prevalence; Prevention; Principal Investigator; Psychostimulant dependence; Public Health; Reaction Time; Recruitment Activity; Research; Research Infrastructure; Risk; SNP array; Sampling; Severities; Signal Transduction; Site; Structure; Testing; Thailand; Universities; Variant; Work; base; bead chip; cohort; cost; design; discount; discounting; endophenotype; exome sequencing; genetic analysis; genetic risk factor; genetic variant; genome analysis; genome wide association study; genome-wide; improved; instrument; meetings; public health relevance; rare variant; response; risk sharing; risk variant; sample collection

 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.

 描述（由申请人提供）：甲基苯丙胺依赖（MD）是一个具有巨大破坏性的公共卫生问题，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，因为与美国相比，泰国的遗传和环境异质性较低，并且在泰国流行病破坏性广泛的背景下，研究成本较低。首席研究员（R. Malison 和 J. Gelernter）已在泰国建立了国际关系并建立了药物依赖（包括医学博士）人类遗传学研究所需的后勤基础设施。利用曼谷现已建立的有效合作（Thanyarak 研究所和朱拉隆功大学），我们收集了初步数据来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表征，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（符合 7 个 MD 标准中不超过 1 个的个体）； 2) 使用全外显子组测序 (WES) 和 GWAS 来识别这个极端表型样本中的罕见和常见变异，然后确认之前收集的来自美国（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。如果获得资助，当前的研究将是迄今为止第一个针对 MD 的 WES 和/或 GWAS 研究。因此，当前研究的结果有可能极大地增进我们对MD遗传风险因素的理解。这些近期信息将提高对MD神经生物学的理解，并最终改进其诊断、治疗和预防方法。