Methamphetamine and Other Substance Use Disorder Genetics in Thailand

项目摘要 甲基苯丙胺使用障碍（MUD）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MUD遗传学的最佳地点， 基因和环境异质性低于美国，研究成本较低， 在一个破坏性和广泛的泰国流行MUD的背景下，主要研究人员已经形成了 国际关系，并建立了人类遗传学研究所需的后勤基础设施， 药物使用障碍，包括MUD，在泰国，如本项目的前期迭代所示;我们收集了 >4000例MUD信息受试者（病例和暴露对照），是承诺样本的两倍。利用我们 建立有效的合作关系（Thanyarak研究所和朱拉隆功大学在曼谷; Suan 我们成功的前期工作支持了该项目的可行性。我们将收集 并表征用于物质使用障碍（SUD）研究的生物库样本，特别是MUD，以及 其他精神疾病和行为。将在曼谷招募6000名受试者（主要在SUD 治疗设施）和4000在清迈（在Suan Prung，主要的精神病医院在北部的 泰国和社区）;总计10，000例，病例数相等，非MUD匹配 对照受试者将通过泰国MIND生物库仪器（泰国版仪器）进行评估 为百万退伍军人计划（MVP）项目开发，来自先前验证的评估模块）。所有 然后，受试者的DNA将在耶鲁中心进行3x低通全基因组测序（WGS）， 基因组分析，称为变体，以及进行全基因组关联分析的数据集。WGS将 允许鉴定常见、罕见和拷贝数变异。我们将与其他人进行荟萃分析。 东亚（例如，中国台湾- 2200例病例，4400例对照）人群，以增加把握度，并进行跨 不同祖先群体的祖先荟萃分析（来自MVP样本和其他大规模生物库 和同伙）。在识别风险变量之后，我们将使用多种方法进行调查， 模型MUD和其他SUD多基因性，以及更广泛的多效性。我们还将调查 MUD的遗传风险与其他精神病学特征之间的关系，并实施因果推理分析， 将MUD的多效性与其他精神病特征和障碍分开。结合我们新招募的 与我们早期的泰国样本和其他不同祖先背景的样本相比，泰国队列将使我们能够 精细绘制MUD相关基因座，并在祖先特异性LD模式中鉴定致病等位基因。数据将 提供给精神病学基因组学联盟，并广泛分享结果。本研究结果 有可能大大推进我们对MUD遗传风险因素的理解，特别是在东部地区， 亚洲人群在遗传学研究中的代表性不足，导致对遗传学的理解有所提高。 本研究旨在研究MUD的神经生物学，并最终改进其诊断，治疗和预防的方法。

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.