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: 9920116
• 负责人: JOEL GELERNTER
• 金额: $ 70.02万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920116
• 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; Infrastructure; 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; Research; Risk; SNP array; Sampling; Severities; Signal Transduction; Site; Structure; Testing; Thailand; Universities; Variant; Work; base; bead chip; cohort; cost; design; discounting; endophenotype; exome sequencing; genetic analysis; genetic risk factor; genetic variant; genome analysis; genome wide association study; genome-wide; improved; instrument; meetings; methamphetamine exposure; public health relevance; rare variant; recruit; 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（由适用提供）：甲基苯丙胺依赖（MD）是一个巨大的破坏性公共卫生问题，在全球范围内激增，包括在美国和亚洲的许多地方。泰国是研究甲基苯丙胺依赖性（MD）遗传学的最佳部位，这是由于与美国相比的精致遗传和环境异质性，并且在遭受毁灭性和广泛的泰国流行的背景下，研究成本较低。主要研究人员（R. Malison＆J。Gelernter）建立了国际关系，并建立了在泰国包括MD在内的人类遗传研究所必需的后勤基础设施。在曼谷（Thanyarak Institute and Chulalongkorn University）中利用现在有效的合作，我们已经收集了初步数据，以支持该项目的主要特定目的的可行性：1）收集和表型来表征适用于MD的极端表型的临床样本，包括1000个严重的MED CASE和MEDS MEDS MEDS MEDS MEDS MED STSM-7/7/7/7/7/7/7/7/7/7/7/7/7/7/7/ 1000甲基苯丙胺暴露但不受影响的对照（符合7个MD标准中的1个个人）； 2）使用整个外显子组测序（WES）和GWAS在此极端表型样本中识别稀有和常见的变体，然后在美国的其他先前收集的苯丙胺依赖性同类群中确认最高的发现（由我们的合作者Cindy Ehlers）和冰岛（我们的合作者Thoregorator Thoregeir thorgeir thorgeirsson收集）；并在我们的欧洲和非裔美国人的可卡因依赖性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风险相关的可遗传性内表型。资助的当前研究将是迄今为止MD的首次WES和/或GWAS研究。这是当前研究的结果，有可能显着提高我们对MD遗传危险因素的理解。这种即时的信息将导致对MD神经生物学的了解，并最终改善了其诊断，治疗和预防的方法。