Long-Term miRNA Changes Predicting Resiliency Factors of Post-Traumatic Stress Disorder in a Large Military Cohort—Millennium Cohort Study

Post-traumatic stress disorder (PTSD) is a complex, debilitating condition prevalent among military personnel exposed to traumatic events, necessitating biomarkers for early detection and intervention. Using data from the Millennium Cohort Study, the largest and longest-running military health study initiated in 2001, our objective was to identify specific microRNA (miRNA) expression patterns associated with distinct PTSD symptom trajectories among service members and veterans and assess their potential for predicting resilience and symptom severity. We analyzed 1052 serum samples obtained from the Department of Defense Serum Repository and linked with survey data collected at baseline and across three follow-up waves (2001-2011), using miRNA sequencing and statistical modeling. Our analysis identified five PTSD trajectories-resilient, pre-existing, new-onset moderate, new-onset severe, and adaptive-and revealed significant dysregulation of three key miRNAs (miR-182-5p, miR-9-5p, miR-204-5p) in participants with PTSD compared to resilient individuals. These miRNAs, which inhibit brain-derived neurotrophic factor (BDNF) and target pathways like NFκB, Notch, and TGF-alpha, were associated with neuronal plasticity, inflammation, and tissue repair, reflecting PTSD pathophysiology. These findings suggest that miRNA profiles could serve as biomarkers for early identification of PTSD risk and resilience, guiding targeted interventions to improve long-term health outcomes for military personnel.