Polygenic Score Identifies Athletes at Increased Risk for Slower Recovery After Sport-Related Concussion: A Concussion Assessment, Research, and Education (CARE) Consortium Study

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BACKGROUND: Emerging evidence suggests that genetic variations contribute to individual differences in concussion recovery. A polygenic score (PGS) can capture the cumulative effect of multiple genetic variants, providing a partial explanation for individual differences in recovery times. OBJECTIVES: In this study, our primary objective was to investigate the association between a PGS and recovery time following sport- or military activity-related concussion to better understand the genetic influences on recovery and inform personalized treatment strategies. METHODS: Genome-wide genotyping data from collegiate athletes and military cadets with confirmed sport- or military activity-related concussions were obtained from the CARE Consortium study (N = 4659). A genome-wide association study (GWAS) was conducted on the discovery cohort (n = 768 samples) to identify single-nucleotide polymorphisms (SNPs) associated with time to return-to-play initiation (RTPi) after concussion using log-logistic accelerated failure time (AFT) models, adjusted for demographic and injury-related factors, and the first five principal components of genetic ancestries. Linkage disequilibrium-clumped SNPs with the lowest p values were selected and further refined using a robust variable selection method under a multivariable AFT model, resulting in the final set of SNPs. The PGS was constructed from this final set of SNPs and validated in an independent validation cohort (n = 262 samples) for time to RTPi. The validation was extended to the biologically relevant slow RTPi outcome (≥ 14 days) using a logistic regression model. We also tested the PGS for association with time to return-to-play (RTP) and slow RTP (≥ 28 days) as secondary outcomes. A Gene Ontology (GO) enrichment analysis was performed on the selected SNPs to identify relevant biological processes. RESULTS: The PGS was constructed using 49 SNPs. We found that higher PGS was significantly associated with a longer time to RTPi after concussion (p = 0.001), where each standard deviation increase in the PGS was associated with a 12% longer time to RTPi. The PGS was significantly associated with a slow RTPi recovery (≥ 14 days), with each standard deviation increase corresponding to an 82% higher odds of delayed recovery (p = 0.002). No significant associations were observed between PGS and RTP outcomes. GO enrichment analysis highlighted synaptic mechanisms related to organization, signaling, and neuronal repair, which are critical for restoring neural communication during the healing process. CONCLUSIONS: Higher PGS is significantly associated with longer recovery time after concussion. This finding provides novel genetic insights for developing personalized treatment strategies to reduce the burden of prolonged recovery from concussion injury.

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