Validation of PTSD signals across multiple biological domains for the development of diagnostic biomarkers for PTSD in military populations to improve clinical care of Veterans

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Post-traumatic stress disorder (PTSD) is likely a systemic illness, affecting not only the brain, but the entire body. Accordingly, efforts to identify biological signals for risk prediction and diagnosis have been performed across multiple biological domains, including –omic assessments of genes and epigenetic changes, and panels including a combination of biomarkers spanning multiple systems. Large-scale genome-wide association studies by the Million Veteran Program (MVP) and Psychiatric Genomics Consortium (PGC) have identified >20 genes associated with PTSD diagnosis/symptoms and developed polygenic risk scores (PRS) to predict risk of developing PTSD after exposure to a traumatic event. Adding to PRS, epigenetic mediation of environmental influences may be a key mechanism of differential susceptibility to PTSD. The largest meta- analysis to date using blood-derived methylation changes prior to and following combat exposure in military cohorts identified several epigenome-wide significant CpGs and differentiated regions. Finally, a recent study aiming at multi-omic biomarker identification for diagnosing warzone- related PTSD has developed a multi-omic diagnostic panel which integrates protein, metabolite, miRNA, methylation and hormone data to predict PTSD diagnosis. Although well powered and developed from unbiased discovery approaches, these biomarkers for PTSD are still preliminary and await systematic validation across specific patient populations such as Veterans seeking care for PTSD at the VA. If the PRS, epigenomic signature, and peripheral biomarker panel are not replicated in treatment-seeking Veterans with PTSD, translating these putative biomarkers from academic investigations to eventual clinical utility for Veteran care will be unlikely. The VA recognizes this need and developed the RFA BX 21-043 which seeks to fund proposals to “validate clinically significant findings such as identification of a therapeutic target or novel biomarker panel based on phenotypic and “omic” data acquired from population studies, … including genetic risk factors, pathophysiological pathways, treatment target identification and biomarker discovery.” The goal of this proposal is to validate the PRS, methylation signature and multi-omic panel in independent cohorts with existing, longitudinal samples collected from treatment-seeking Veterans. Results of these studies will be highly informative for development of these biomarkers for precision medicine applications.