The pediatric buccal epigenetic clock identifies significant ageing acceleration in children with internalizing disorder and maltreatment exposure
Felix Dammering, Jade Martins, Katja Dittrich, Darina Czamara, Monika Rex‐Haffner, Judith Overfeld, Karin de Punder, Claudia Buß, Sonja Entringer, Sibylle Winter, Elisabeth B. Binder, Christine Heim
Abstract
BACKGROUND: Studies reporting accelerated ageing in children with affective disorders or maltreatment exposure have relied on algorithms for estimating epigenetic age derived from adult samples. These algorithms have limited validity for epigenetic age estimation during early development. We here use a pediatric buccal epigenetic (PedBE) clock to predict DNA methylation-based ageing deviation in children with and without internalizing disorder and assess the moderating effect of maltreatment exposure. We further conduct a gene set enrichment analysis to assess the contribution of glucocorticoid signaling to PedBE clock-based results. METHOD: DNA was isolated from saliva of 158 children [73 girls, 85 boys; mean age (SD) = 4.25 (0.8) years] including children with internalizing disorder and maltreatment exposure. Epigenetic age was estimated based on DNA methylation across 94 CpGs of the PedBE clock. Residuals of epigenetic age regressed against chronological age were contrasted between children with and without internalizing disorder. Maltreatment was coded in 3 severity levels and entered in a moderation model. Genome-wide dexamethasone-responsive CpGs were derived from an independent sample and enrichment of these CpGs within the PedBE clock was identified. RESULTS: = 1.65*10-6). Among the 94 CpGs of the PedBE clock, 18 (19%) were responsive to dexamethasone. CONCLUSION: Using the novel PedBE clock, we show that internalizing disorder is associated with accelerated epigenetic ageing in early childhood. This association is moderated by maltreatment severity and may, in part, be driven by glucocorticoids. Identifying developmental drivers of accelerated epigenetic ageing after maltreatment will be critical to devise early targeted interventions.