Genomic Signature Associated with Postconcussive Symptoms in Pediatric Mild Traumatic Brain Injury

Genetic contributions to the outcomes of pediatric mild traumatic brain injury (mTBI) are unclear. The current study applied a genomic signature approach to characterize biological processes critical to variation in persisting symptoms after concussion (PSaC). This planned substudy used data from a prospective cohort observational study, Advancing Concussion Assessment in Pediatrics. Participants aged 8-16.99 years with mTBI or orthopedic injury (OI) were recruited from five emergency departments in Canada between September 2016 and December 2018. Parents completed the Health and Behavior Inventory at 1 week, 1 month, and 3 and 6 months postinjury. Child saliva samples were used for DNA extraction and genotyping. The final genomic dataset included 122,701 variants in 17,212 genes. A systems biology analysis identified a case set of 26,642 variants in 2299 genes likely to be related to brain injury recovery. The same analysis identified a control set of variants/genes not enriched in any of the biological processes associated with brain injury recovery. Linear models examined the interaction between group (mTBI vs. OI) and genetic variant as a predictor of cognitive and somatic PSaC severity at the four follow-up assessments. To test for a genomic signature, we compared the number of nominally significant (p < 0.05) variants associated with group differences in PSaC in the case set to the number of associations meeting the same criteria in >10,000 matched runs of the control set. When the number of nominal associations in the case genes exceeded the 95th percentile expected by chance, they were considered enriched for genes/variants associated with PSaC severity. Participants included 967 children (633 mTBI, 334 OI; median [interquartile range {IQR}] age, 12.3 [10.5-14.3] years; 562 [58.1%] male); 891 provided a saliva sample, genotyping was completed for 720 samples, and 686 (462 mTBI, 224 OI) passed quality control. The aggregate signal from the gene-case set accounted for substantial variability in group differences in somatic symptom severity and modest variability in cognitive symptom severity, especially at 1-week and 1-month postinjury. Although the specific genes varied by symptom type and time postinjury, suggesting nonidentical genomic signatures, they shared overlapping biological processes. The findings demonstrate polygenic contributions to PSaC severity after pediatric mTBI. Specific genomic signatures vary by symptom type and time postinjury but share common biological pathways and processes. A better understanding of genomic contributions to pediatric mTBI outcomes should eventually yield more individualized management approaches.