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

Child maltreatment is a leading cause of pediatric morbidity and mortality, 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 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, followed by near-promoter gene set enrichment analysis. Abuse was associated with methylation at 11 sites (q<0.10), including enhancers of neuroblast differentiation-associated <i>AHNAK</i>, immunomodulators <i>SCGB1A1</i> and <i>CCL26</i>, exon 5 of <i>LAMP1</i>, essential for lysosomal function and cytotoxicity, and <i>RGS7</i>, a GTPase essential for synaptic transmission. Enriched biological processes included cranial skeletal system and connective tissue development, neural structure and function, immune regulation, gene expression, and metabolism. Our findings suggest that early abuse may epigenetically affect both proximal injury responses and longer-lived systemic biological dysregulation.