PROJECT SUMMARY / ABSTRACT Post-traumatic stress disorder (PTSD) is a common and debilitating mental disorder that has a profound public health impact and for which the disease burden falls disproportionately on African Americans (AAs). Socially adverse experiences of discrimination and isolation, stressful life events, and low socioeconomic position (SEP) have a profound impact on mental and physical health, with AAs being more likely to encounter many of these exposures; yet how these exposures become translated into ill health, in particular poor mental health, is unclear. To address this gap in knowledge, this application seeks to determine whether social adversity among AA residents of Detroit impacts glucocorticoid receptor regulatory network (GRRN) DNA methylation to lay the foundation for future risk of psychopathology. Exposure to stressful and traumatic events produces a physiologic cascade that includes epigenetic modification of genes whose activity contributes to psychopathological development. In particular, stress hormones (e.g. glucocorticoids) and genomic factors associated with them have been strongly linked to etiology of PTSD and other stress-related mental disorder. It remains unknown to what extent socially adverse exposures such as low SEP, discrimination, loneliness, and stressful life events impact DNA methylation in genes belonging to this pathway. We hypothesize that DNA methylation of GRRN genes in leukocytes is associated with prospective risk of PTSD and traumatic stress in Detroit-dwelling AAs, due to their role in the physiology of stress in both central and peripheral tissues. We further hypothesize that exposure to socioeconomic and psychosocial stressors impact DNA methylation variation in GRRN genes, laying the foundation for vulnerability to psychopathology, including post-traumatic stress symptom severity, depression symptom severity, and generalized anxiety symptom severity. This proposal brings together a strong investigative team with extensive expertise in social epidemiology, epigenetics, PTSD, and AA health. Our team will leverage data from a comprehensive, population based cohort study of mental health in AAs, the Detroit Neighborhood Health Study (DNHS). Results will be replicated using data from two independent cohorts, the Grady Trauma Project and the Predictive Biomarkers of PTSD Project. In addition, in vitro cell culture experiments will be leveraged to test GRRN dysregulation in neuronal cell lines, and will test the functional significance of GRRN DNA methylation variation.