397 - Epigenetic Responses to Abusive versus Accidental Injury in Young Children: An Epigenome Wide Association Study

Publication Number: 397.4931

Kyle A. Campbell, Emory University, ANN ARBOR, MI, United States; MARY Clyde Pierce, Ann & Robert H. Lurie Children's Hospital of Chicago, EVANSTON, IL, United States; Todd Everson, Emory University, Atlanta, GA, United States; Kathi L. Makoroff, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Audrey Raut, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States; Kim Kaczor, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States

Background: Child maltreatment is a pervasive problem leading to increased morbidity and mortality across the lifespan. DNA methylation (DNAm) represents a potential epigenetic mechanism by which differential health outcomes may be realized.

Objective: Our objective was to characterize the responses to abusive versus accidental injury in young children with a cross-sectional DNAm epigenome-wide association study (EWAS) meta-analysis.

Design/Methods: We collected buccal swabs for DNAm microarrays from 175 children < 4 years of age with traumatic injuries at two children’s hospitals. A child abuse assessment team or medical expert panel classified injuries as abusive or accidental. Linear EWAS models were stratified by major injury subtypes followed by fixed effect meta-analysis and rank-based gene set enrichment analysis. Covariates included sex, insurance, psychosocial risk score, race, ethnicity, and both DNAm-derived cell composition and surrogate variable estimates for confounding. Statistical significance was assessed at false discovery adjusted q-value < 0.25.

Results: We conducted an EWAS fixed effect meta-analysis across 472,370 loci of three injury groups: traumatic brain injury (TBI) among infants 0-12 months (abuse=20, non-abuse=76), long-bone fractures without TBI among infants 0-12 months (abuse=7, non-abuse=11), and an earlier pilot study of children < 4 years with TBI, fractures, or bruising only (abuse=22, non-abuse=39). Abuse was associated with differential DNAm at 42 loci including epigenetic regulators CBX2 (q=0.14), ZNF579 (q=0.21), and EDC4 (q=0.23); microtubule/cytoskeleton genes PKP1 (q=0.21), NINL (q=0.22), and CFAP157 (q=0.23); inflammatory cytokine CCL26 (q=0.15); and the xenobiotic catabolism gene AOX1 (q=0.21). These loci were enriched for 73 biological processes, including forebrain neuron differentiation (q=0.005), neuromuscular junction development (q=0.02), messenger RNA decay (q=0.02), fatty acid biosynthesis (q=0.02), wound healing (q=0.13), and immunoglobulin-mediated immune regulation (q=0.13).

Conclusion(s): Among young children with traumatic injuries, abuse classification was associated with differential DNAm at loci pertaining to epigenetic regulation, neurodevelopment, wound healing, and other biological processes. Our findings suggest that early-life abuse may not only differentially affect proximal injury responses such as wound healing and inflammation, but also have systemic effects on transcriptional and immune regulation, metabolism, and neurodevelopment.