Epigenetic Responses to Abusive versus Accidental Injuries in Children: A Cross-sectional Epigenome Wide Association Meta-analysis

Child maltreatment is a pervasive problem leading to increased morbidity and mortality across the lifespan, potentially propagated by DNA methylation (DNAm) changes. We conducted an EWAS meta-analysis (n=175, 554,979 Illumina EPICv1/EPICv2 sites) in buccal swabs from three hospital-based studies of young children with traumatic injuries, stratified by study group to include 1) any traumatic injury, 2) fractures, and 3) traumatic brain injuries. Empirical bayes-moderated linear models tested differential DNAm with M-values. We identified abuse-associated pathways with rank-based promoter gene set enrichment analysis. Abuse was associated with methylation at 11 sites (false-discovery q<0.10), including enhancers of neuroblast differentiation-associated AHNAK and the immunomodulators SCGB1A1 and CCL26 as well as exon 5 of LAMP1, essential for lysosomal function and cytotoxicity. Several of the most enriched biological processes included injury-affected cranial skeletal system and connective tissue development, neural structure and function, immune regulation, gene expression regulation, and metabolism. Our findings suggest that early-life abuse may epigenetically affect both proximal injury responses and longer-lived systemic biological dysregulation.