Polygenic regulation of PTSD severity and outcomes among World Trade Center responders

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition occurring in individuals exposed to trauma. The study of PTSD is complicated by highly heterogeneous presentations and experiences of trauma. Here, we studied genetic correlates of PTSD and resilience among a group of responders to the World Trade Center (WTC) 9/11/2001 attacks. This cohort represents a unique opportunity to study genetic risk factors for PTSD, and resilience, following a single, shared, well-documented trauma. We calculated polygenic risk scores associated with PTSD among these 375 individuals, and demonstrated a significant genetic association with social cognition traits, brain volumetric phenotypes, and PTSD-GWAS-derived PRS. Our results demonstrate significant genetic regulation of PTSD severity (CAPS scores) and chronicity (past-month CAPS). PRS derived from GWAS of ADHD, ASD, and brain imaging phenotypes (Amygdala and Putamen volume) were associated with multiple PTSD traits in this study. Interestingly, we find greater genetic contribution to PTSD among cases compared to our full cohort. In addition, we tested for associations between exposures to traumatic stressors, including WTC-related exposures, childhood trauma, and traumatic life events since 9/11. Together, polygenic risk and exposures to traumatic stress explain [~]45% of variance in lifetime CAPS among the full cohort (R2=0.454), and [~]48% of variance in past-month CAPS (R2=0.480). These participants represent a highly vulnerable population, with exposures to severe trauma during 9/11 and the following days. Identifying individuals at heightened risk for PTSD, or who may be suited to particular therapies, is of special importance and relevance in this group. In particular, the identification of MRI imaging phenotypes indicates that coupling of neuroimaging with genetic risk score calculations may predict PTSD outcomes.