M79 - GENOME-WIDE DNA METHYLATION SIGNATURES OF AGGRESSION RISK IN CHILDREN

Abstract

Background Child abuse is a highly prevalent public health problem and a risk factor for numerous psychopathological disorders. Early physical abuse and neglect have been associated with an increased risk of childhood conduct disorders. However, not all children exposed to abuse develop aggression later in life, suggesting interplay between genetic and environmental factors in the predisposition to aggression. Methods This study investigated genome-wide DNA methylation changes associated with aggressive behavior in children. A total of 105 9–15 years old children of European ancestry were included in the study (56% female, 12 ± 1.8 mean of age). The Illumina Infinium 450 K Methylation BeadChip array was used to conduct the methylation study using the genomic DNA extracted from saliva samples. Aggression was evaluated using the Child Behavior Checklist (CBCL) Scores ranged from 50–87 (mean: 57 ± 10.5), with 39% of the sample meeting the clinical cut-off (≤ 63). We conducted a linear mixed effects model to examine the main effect of trauma, main effect of DNA methylation and an interaction term, and adjusted for age, sex, cell composition, and 10 principal components (PCs) estimated using Barfield et al. method. Significance was set to 5.0×10-7 to correct for multiple comparisons. Results A total of eight methylation sites were genome-wide significant (GWS) for the DNA methylation term after adjusting for age, sex, cell type composition and 10 PCs. From these sites, cg18438793 (p=2.58×10-7) located within the hippocalcin like 4 (HPCAL4) gene is of importance due to its role in neuronal development and calcium signaling and brain-specific gene expression. Further, expression of this gene is induced after fear conditioning in the lateral amygdala of mice. Additional sites (p value range: 10-10 – 10-7) are involved in axon guidance, myelination and transcriptional regulation. Discussion This study increases our understanding of the epigenetic changes associated with aggression in children. By identifying predictors of aggression in early life, this study may provide novel tools to improve treatment and preventive interventions for aggression risk in children.