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.