Interactions between mild traumatic brain injury and genetics perturb neuronal and glial pathways and networks relevant to learning and memory in ABCD study

Mild traumatic brain injury (mTBI) disproportionately affects children and adolescents and has been associated with poorer neurocognitive performance, but the variability in acute and chronic symptoms presents challenges in understanding the biological mechanisms underlying symptom heterogeneity and predicting these effects in clinical settings. We hypothesized that genetic factors interact with mTBI to determine vulnerability or resistance to neurological dysfunction post-mTBI. We leveraged the baseline Adolescent Brain Cognitive Development (ABCD) cohort to conduct a gene-by-mTBI genome-wide association study (GWAS) to study the interaction between mTBI and genetics in learning and memory compared to orthopedic injury controls. The GWAS revealed significant biological pathways involved in mitochondrial function and synaptic signaling that are enriched for SNPs showing evidence of interaction with mTBI. Integration of the gene-by-mTBI pathways from ABCD with cell-type specific gene regulatory networks built from single-cell RNA sequencing data from the Allen Brain Atlas uncovered key driver genes such as APP, MAPT, and MOG which coordinate between cell types in hippocampus and cortex to regulate these pathways. Lastly, we performed polygenic risk score (PRS) analysis on these pathways to assess their clinical value in predicting learning and memory outcomes in the ABCD cohort, revealing a statistically significant contribution but limited clinical benefit. Our findings provide novel insights into the genetic modifiers of mTBI pathology and propose potential therapeutic candidates at pathway and network levels. Author SummaryMild traumatic brain injury (mTBI), or concussion, is prevalent in adolescents and can have lasting impact on brain development, learning, and memory. However, the high variability in injury outcomes presents major challenges in predicting the specific recovery trajectories in individual children. Our study examines the entire genome to uncover genetic factors underlying mTBI response that determine an individuals vulnerability to cognitive deficits. By investigating the interaction between genetics and injury, we aim to pinpoint how genetic predispositions affect biological processes in brain injury recovery to determine disease severity. Our findings revealed certain genetic factors that are related to learning and memory in individuals with mTBI, but not in those with orthopedic injuries. These factors affect crucial areas of brain recovery, including neuronal repair and metabolism. We identified the core genes that coordinate across different brain cell types to affect these biological pathways. Finally, we leveraged these genetic factors to predict learning and memory performance in mTBI patients. By examining the biological mechanisms driven by the genetic-mTBI interaction, we provide novel insights into the complex relationships between genetics, brain injury, and cognitive function. Our study provides a data-driven framework to understand how genetic and environmental factors interact to influence disease outcomes.