Duration of contact sports play associated with aberrant DNA methylation in human frontal cortex

Repetitive head impacts (RHI), primarily through contact sports play and military service, are a recognized risk factor for cognitive and behavioral symptoms, as well as progressive neurodegenerative diseases such as chronic traumatic encephalopathy. While altered DNA methylation has been linked to environmental exposures and neurodegeneration, its association with RHI remains unknown. In this study, we investigated whether duration of contact sports play in a community-based aging cohort is associated with altered DNA methylation patterns. Reduced representation bisulfite sequencing on human dorsolateral frontal cortex identified 461 genome-wide significant CpG sites associated with duration of contact sports play, spanning 13 genes of which the majority were hypomethylated. The hypomethylation pattern was largely replicated in an independent cohort. Notably, CAMK2B, B4GALT6, and TLR2, were hypomethylated and upregulated in the cortical sulcus of the DLFC in individuals with RHI exposure from contact sports. Furthermore, alterations of CAMK2B and B4GALT6 were observed in CTE cases. Together, these findings reveal distinct, region-specific epigenetic changes associated with contact sports exposure and provide new insights into the molecular mechanisms underlying RHI-related sequalae.