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 for 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 was derived from summary statistics of large genome-wide association studies of Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, and major depressive disorder (MDD); 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 (R = 1.11%; p = 3.37 × 10). Enrichment analysis identified two significant Gene Ontology (GO) terms related to this result: GO:0050839∼Cell adhesion molecule binding (p = 8.9 × 10) and GO:0050905∼Neuromuscular process (p = 9.8 × 10). 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.

Polygenic Risk and Neural Substrates of Attention-Deficit/Hyperactivity Disorder Symptoms in Youths With a History of Mild Traumatic Brain Injury

“…This suggests that in individuals who experience TBI, the physical insult to the brain and resulting alterations in structure and function may be influential contributors to the presentation of post TBI ADHD symptoms, whereas additive genetic predisposition contributes to developmentally acquired ADHD. These results oppose the idea that those with higher polygenic score may be more vulnerable to developing ADHD symptoms following brain injury but are consistent with a recent study of soldiers with TBI, that found that the genetic predisposition to persistent post-concussion symptoms following TBI does not have substantial overlap with genetic predisposition to neurodegenerative and psychiatric diseases (42).…”

Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder

“…Our investigation was conducted using summary statistics from GWAS of psychiatric disorders and testing for enrichment of positive selection signatures, using the same concept as is applied in high-resolution polygenic risk score analysis [ 26 , 27 ]. The positive selection signatures were identified using the hierarchical boosting (HB) algorithm, which is a machine-learning classification framework that combines the functionality of several selection tests to uncover different genetic features that are expected under selective sweeps [ 28 ].…”

Allergy-specific Phenome-Wide Association Study for Immunogenes in Turkish Children

“…Specifically, the genes involved in immune response appeared to play a relevant role in the processes linked to allergic airway inflammation, lung function, and eczema-wheezing comorbidity. Further investigations of large cohorts, such Mendelian randomization studies 44 and polygenic risk score analysis 45 , can dissect how the genetics of lower lung function affects the risk of allergic disease.…”