Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy...

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N _total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.