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.

Public Health Relevance

Methamphetamine addiction is a hugely destructive public health problem that is surging worldwide, including in many parts of the US and Asia, where Thailand is one of the most profoundly affected countries worldwide. Although a significant portion of the risk for methamphetamine addiction is genetic, no genes for the disorder have been identified to date, in large part because of insufficient study of large enough numbers of people who are affected (a major advantage of conducting such work in Thailand) and the failure to use modern genome wide approaches. The identification of genes underlying the risk for methamphetamine addiction will shed light on the underlying causes of the disorder, and in turn, lead to improvements in our understanding and treatment, and ultimately prevention, of this devastating problem.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Behavioral Genetics and Epidemiology Study Section (BGES)
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Pollock, Jonathan D
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Yale University
Schools of Medicine
New Haven
United States
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Gelernter, Joel; Zhou, Hang; Nuñez, Yaira Z et al. (2018) Genomewide Association Study of Alcohol Dependence and Related Traits in a Thai Population. Alcohol Clin Exp Res 42:861-868