Methamphetamine and Other Substance Use Disorder Genetics in Thailand

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.