Cross-phenotype Polygenic Risk Score Analysis of Persistent Post-Concussive Symptoms in U.S. Army Soldiers with Deployment-acquired Traumatic Brain Injury

Abstract Traumatic brain injury (TBI) contributes to the increased rates of suicide and post-traumatic stress disorder in military personnel and veterans; and it is also associated with the risk of neurodegenerative and psychiatric disorders. A cross-phenotype high-resolution polygenic risk score (PRS) analysis of persistent post-concussive symptoms (PCS) was conducted in 845 U.S. Army soldiers who sustained TBI during their deployment. We used a prospective longitudinal survey of three Brigade Combat Teams to assess deployment-acquired TBI and persistent physical, cognitive, and emotional PCS. PRS were derived from summary statistics of large genome-wide association studies of Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, and major depressive disorder; and for years of schooling, college completion, childhood intelligence, infant head circumference (IHC), and adult intracranial volume. Although our study had more than 95% of statistical power to detect moderate-to-large effect sizes, no association was observed with neurodegenerative and psychiatric disorders, suggesting that persistent PCS does not share genetic components with these traits to a moderate-to-large degree. We observed a significant finding: subjects with high IHC PRS recovered better from cognitive/emotional persistent PCS than the other individuals (R2= 1.11%; p=3.37*10-3). Enrichment analysis identified two significant Gene Ontology (GO) terms related to this result: GO:0050839~Cell adhesion molecule binding (p=8.9*10-6) and GO:0050905~Neuromuscular process (p=9.8*10-5). In summary, our study indicated that the genetic predisposition to persistent PCS after TBI does not have substantial overlap with neurodegenerative and psychiatric diseases; but mechanisms related to early brain growth may be involved. KEYWORDS: GENETIC FACTORS; MILITARY INJURY; TRAUMATIC BRAIN INJURY