ABSTRACT Polygenic risk score for posttraumatic stress disorder (PTSD-PRS), an aggregate of individual genetic variants associated with the disorder, can help identify vulnerable individuals and clarify biological mechanisms underpinning PTSD, such as systemic inflammation. However, it remains unclear whether PTSD-PRS is predictive of PTSD in civilians with occupational exposures (e.g. police officers), and whether it predicts the long- term course of PTSD (e.g., resilient, chronic, worsening, and improving trajectories). Furthermore, the nature of association between PTSD and inflammation remains poorly understood, and genetics can clarify the direction of this link. Therefore, the proposed project aims to first test whether PTSD-PRS is associated with PTSD diagnosis and 18-year symptom course following trauma exposure in responders to the World Trade Center (WTC) attacks. Second, it aims to investigate the contribution of genetic vulnerability to the association between PTSD and plasma levels of pro-inflammatory marker C-reactive protein (CRP). To this end, a large sample of responders to the WTC attacks (N=8,000, 90.2% male, 87.7% Caucasian, 67.0% in law enforcement, 19.9% lifetime WTC-related PTSD diagnosis) from the Long Island WTC Health Program will be genotyped. The level of disaster exposure and an extensive prospective psychiatric and medical history is available for this cohort from electronic medical records collected since 2002. All blood samples are biobanked, further rendering the proposed study highly cost effective and feasible. Blood will additionally be assayed for CRP levels concurrent with the most recent PTSD assessment. The proposed study will inform the translation of cutting-edge genetic tools to health research in an occupational cohort of police and non-traditional responders. Improved understanding of PTSD genetics holds much promise for reducing burden of this disorder in occupational cohorts by identifying people at risk who would benefit from more resilience training and frequent screenings. The study will also provide insights into the association between PTSD and inflammation, elucidating etiologic pathways to the disorder and informing treatment approaches.