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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.

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N=1,016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with highest lifetime CAPS score (FDR-corrected p<0.05), and 31 genes associated with past-month CAPS. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our overall analysis. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were down-regulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

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