Transcriptomic Insights into the Co-occurring Psychological Symptoms and Cardiovascular Risks Among Military Service Members and Veterans with Mild Traumatic Brain Injury: A LIMBIC-CENC study

Service members and veterans (SMVs) are at higher risk for post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), which are detrimental to cardiovascular health (CVH) and brain health. This study aimed to identify gene expression signatures in SMVs associated with the co-occurrence of psychological symptoms, specifically PTSD/MDD, and cardiovascular risk factors, while exploring shared biological pathways that may link these conditions to broader heart and brain health. This study used baseline data from the Long-term Impact of Military-related Brain Injury Consortium—Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) study. Participants aged>20 with a mild traumatic brain injury history but no prior cardiovascular disease diagnosis were included. Gene expressions were compared between individuals with PTSD and/or MDD with poor CVH (combined case), and those without PTSD/MDD and a high resilience score, with good CVH (healthy comparison). Total RNA-sequencing of peripheral whole blood was conducted to identify differentially expressed genes (DEGs). DEGs with FDR-adjusted p-value<0.05 and |log2 fold change|≥0.5 were included in downstream analyses, including canonical pathways and network analysis using Ingenuity Pathway Analysis software. A total of 85 participants were included: 56 in the combined cases and 29 in the comparisons, with mean ages of 39.4 (± 8.7) and 43.1 (± 9.6), respectively. We identified 54 DEGs, of which 47 were up-regulated, including S100A8 and S100A12, and seven were down-regulated, including GATA2. Pathway analysis revealed that immune activation, metabolic stress, endothelial dysfunction, and inflammatory signaling are common. These findings suggest that SMVs with concurrent PTSD/MDD symptoms and poor CVH exhibit distinct immune-inflammatory signatures that may link to heart and brain vulnerability. Targeting these shared pathways may enable integrated strategies for biomarker discovery and early intervention in high-risk populations.