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Methamphetamine and Other Substance Use Disorder Genetics in Thailand

泰国的甲基苯丙胺和其他药物使用障碍遗传学

基本信息

批准号：
10585560
负责人：
JOEL GELERNTER
金额：
$ 86.18万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585560
关键词：
Address African ancestry Asia Asian Asian ancestry Asian population Behavior Biology Chromosome Mapping Clinical Collaborations Collection Communities Copy Number Polymorphism Country DNA Data Data Set Dedications Diagnosis Disease Drug Use Disorder Drug abuse East Asian Epidemic European ancestry Faculty Genetic Genetic Diseases Genetic Risk Genetic study Genomics Genotype Grant Heritability Heterogeneity Hospitals Human Human Genetics Individual Infrastructure International Knowledge Maps Medicine Memory Mental Health Mental disorders Meta-Analysis Methamphetamine Methamphetamine use disorder Methods Modeling Neurobiology Participant Pattern Pharmaceutical Preparations Phenotype Population Prevention Principal Investigator Psychiatric Hospitals Psychopathology Public Health Research Sampling Sampling Studies Site Substance Use Disorder Taiwan Thailand Time Underrepresented Populations Universities Variant Veterans Work biobank causal variant cohort cost disorder control disorder risk gene discovery genetic analysis genetic risk factor genome analysis genome sequencing genome wide association study genome-wide improved in silico instrument neuroimaging phenome pleiotropism programs psychiatric genomics recruit risk variant sample collection substance use trait whole genome

项目摘要

Project Summary Methamphetamine use disorder (MUD) 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 MUD, owing to lower genetic and environmental heterogeneity than in the US, and lower research costs, in the greater context of a devastating and widespread Thai epidemic of MUD, The Principal Investigators have formed the international relationships and established the logistical infrastructures necessary for human genetic studies of drug use disorders, including MUD, in Thailand, as shown during the prior iteration of this project; we collected >4000 MUD-informative subjects (cases and exposed controls), twice the promised sample. Leveraging our established and effective collaborations (Thanyarak Institute and Chulalongkorn University in Bangkok; Suan Prung Hospital in Chiang Mai), our successful prior work supports the feasibility of this project. We will collect and characterize a biobank sample for studies of substance use disorders (SUDs), especially MUD, as well as other psychiatric disorders and behaviors. 6000 subjects will be recruited in Bangkok (primarily at SUD treatment facilities) and 4000 in Chiang Mai (at Suan Prung, the major psychiatric hospital in the north of Thailand and in the community); 10,000 in total, balanced with equal numbers of cases and non-MUD matched controls. Subjects will be evaluated via the Thai MIND biobank instrument (the Thai version of an instrument developed for a Million Veteran Program (MVP) project from previously-validated assessment modules). All subjects' DNA will then be subjected to 3x low-pass whole-genome sequencing (WGS) at the Yale Center for Genome Analysis, variants called, and the dataset subjected to genomewide association analyses. WGS will allow the identification of common, rare, and copy number variants. We will undertake meta-analysis with other East Asian (e.g. Taiwan – 2200 cases, 4400 controls) populations to increase power, and conduct trans- ancestry meta-analyses with diverse ancestry groups (from the MVP sample and other large-scale biobanks and cohorts). Following the identification of risk variants, we will use multiple approaches to investigate and model MUD and other SUD polygenicity, and pleiotropy more broadly. We will also investigate the relationship between genetic risk for MUD and other psychiatric traits, and implement causal inference analysis to disentangle the pleiotropy of MUD with other psychiatric traits and disorders. Combining our newly-recruited Thai cohort with our earlier Thai sample and other samples of diverse ancestral backgrounds will permit us to fine-map MUD-associated loci and identify causal alleles across ancestry-specific LD patterns. Data will be made available to the Psychiatric Genomics Consortium and results shared broadly. Results from this study have the potential to advance greatly our understanding of genetic risk factors for MUD, especially in East Asian populations underrepresented in genetic studies, leading to an improved understanding of the neurobiology of MUD and, ultimately, improved approaches to its diagnosis, treatment, and prevention.

项目摘要甲基苯丙胺使用障碍(MUD)是一个破坏性极大的公共卫生问题，正在全球范围内激增，包括在美国和亚洲的许多地区。泰国是研究泥浆遗传学的最佳地点，因为比美国更低的遗传和环境异质性，以及更低的研究成本在泰国毁灭性和广泛流行的泥浆疫情的背景下，首席调查人员已经成立了国际关系，并建立了人类基因研究所需的后勤基础设施在泰国的药物使用障碍，包括泥浆，如在这个项目的前一次迭代中所示；我们收集了 &gt；4000名提供泥浆信息的受试者(病例和暴露的对照)，是承诺样本的两倍。利用我们的已建立和有效的合作(坦亚拉克研究所和曼谷的朱拉隆功大学；Suan 清迈的Prung医院)，我们成功的前期工作支持了这个项目的可行性。我们会收集以及用于物质使用障碍(SODS)研究的生物库样本的特征，特别是泥浆，以及其他精神障碍和行为。将在曼谷招募6000名受试者(主要在南德治疗设施)和4000人(在清迈北部的主要精神病院Suan Prung 泰国和社区)；总共10,000例，病例数量相等，非泥浆匹配控制。受试者将通过泰国思维生物库仪器(泰国版本的仪器)进行评估根据先前验证的评估模块为百万退伍军人计划(MVP)项目开发)。全受试者的DNA随后将在耶鲁大学中心接受3倍低通全基因组测序(WGS) 基因组分析，称为变异体，以及接受全基因组关联分析的数据集。WGS将允许识别常见的、罕见的和拷贝数变体。我们将与其他公司进行荟萃分析东亚(如台湾-2200例，4400例对照)人口增加权力，并进行跨国不同祖先群体的祖先荟萃分析(来自MVP样本和其他大型生物库和队列)。在确定风险变量之后，我们将使用多种方法来调查和模拟泥浆和其他南泥的多源性，以及更广泛的多效性。我们还将调查两国关系 MUD的遗传风险与其他精神特征之间的关系，并进行因果推断分析将MUD的多效性与其他精神特征和障碍分开。结合我们新招募的与我们早先的泰国样本和其他具有不同祖先背景的样本的泰国队列将使我们能够精细绘制MUD相关基因座图，并识别祖先特定LD模式的因果等位基因。数据将是提供给精神病学基因组学联盟，并广泛分享结果。这项研究的结果有可能极大地提高我们对MUD的遗传风险因素的理解，特别是在东部亚洲人群在遗传学研究中的代表性不足，导致对泥浆的神经生物学，并最终改进了其诊断、治疗和预防的方法。