Gene-Environment Interaction for Cannabis Use Disorders in Blacks and Whites in the U.S.

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 DESCRIPTION (provided by applicant): Gene-Environment Interaction for Cannabis Use Disorders in Blacks and Whites in the US. 40-50% of US adults have used cannabis, and ~1/3 of users experience at least one cannabis use disorder (CUD) symptom which increases risk for many negative outcomes, including problematic substance use behaviors (SUB). Recent data has shown that the prevalence of CUD is growing faster among African- Americans (AA) than all other groups in the US. There are critical gaps in US SUB etiology that gene- environment interaction (GxE) research can begin to address: (1) There are no large-scale genetic studies of CUD in AAs, creating a gap in understanding the genetic etiology of CUD in the US. AAs have greater genetic diversity than Whites/European Americans (EA) due to evolutionary differences in allele frequencies and linkage disequilibrium (LD). Thus, genetic association studies comparing AAs and EAs are critically needed to further understanding in AAs generally, and in the US. Social context (trauma, religiosity) modifies the strength of genetic risk for SUB. However, (2) there are no GxE studies of CUD. Moreover, few studies examine GxE of SUB in AAs, and no study has examined if GxE effects of SUB differ between AAs and EAs, which might be expected due to known AA/EA differences in ancestry, rates and types of exposure to trauma and religiosity, and impact on SUB. (3) GxE research on CUD has yet to employ new developments in polygenic strategies that incorporate known biological systems. To date, only two studies of any SUB used polygenic strategies in the context of GxE, mainly because few studies have sufficiently large samples needed, and concerns about the non-translatability of polygenic scores into specific genetic/neurobiological targets. These concerns are mitigated with pathway-based set tests, which aggregate genetic variants across candidate biological pathways to better reflect the underlying structure of CUD. The revised K01 proposal delineates the training required for me to become an independent investigator conducting interdisciplinary research that identifies the mechanisms via which psychosocial factors modify genetic and neurobiological risk for SUB in the diverse US population. My research will examine if trauma and/or religiosity modifies genetic risk for CUD in both AAs and EAs in a new US nationally representative sample, the NESARC-III (n=36,309; 20%:7,262 AA), which includes genotypic data and dimensional measures of cannabis use frequency, and DSM-IV and 5 CUD. Three areas of advanced training will enable me to carry out these goals: (1) Phenotypic Measurement of SUB, (2) Addictions Neuroscience, and (3) Trauma and Resilience. The proposed activities are ambitious, but feasible, given my record of productivity, mentorship by an interdisciplinary team of experts (Hasin (primary mentor), Martinez, Koenen) at Columbia University, consultation with Dr. Agrawal in CUD Genetics and Dr. Fullilove in the Responsible Presentation of Genetic Differences by Race, and K01 protected time (5 yrs) for research and training, and the development of an R01.