Inter-individual differentially methylated region-targeted EWAS reveals epigenetic signatures of early childhood adversity

<h4>Aims</h4>Adverse childhood experiences (ACEs), especially in early life, can affect psychosocial development and increase lifelong risk for mental disorders. ACEs are also known to induce persistent epigenetic changes. This study aimed to explore ACE-associated DNA methylation signatures using an epigenome-wide association study (EWAS) targeting inter-individual differentially methylated regions (DMRs).<h4>Methods</h4>We developed a targeted capture probe system covering ~1.3 million CpG sites within inter-individual DMRs. This system was applied to salivary DNA from drug-naïve children aged 6-12 years with exposure to multiple early-life ACEs (<i>n</i> = 23) or who had no ACEs (<i>n</i> = 21).<h4>Results</h4>We identified 15 novel DMRs significantly associated with ACEs. A cluster of six CpG sites within an exon of the <i>EIF4G2</i> gene showed consistently increased methylation in children with ACEs, with strong inter-site correlations. Enrichment analysis indicated that genes near these DMRs are involved in neurodevelopmental disorders, suggesting that early adversity may influence brain development through epigenetic mechanisms.<h4>Conclusion</h4>Our findings suggest that early adversity may contribute to lasting epigenetic modifications in children. The identified DMRs may serve as noninvasive biomarkers for retrospective ACE assessment and provide insights into the biological embedding of early-life stress.