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 Children with internalizing disorder exhibited significant acceleration of epigenetic ageing as compared to children without internalizing disorder (F 1,147 = 6.67, p = .011). This association was significantly moderated by maltreatment severity (b = 0.49, 95% CI [0.073, 0.909], t = 2.322, p = .022). Children with internalizing disorder who had experienced maltreatment exhibited ageing acceleration relative to children with no internalizing disorder (1–2 categories: b = 0.50, 95% CI [0.170, 0.821], t = 3.008, p = .003; 3 or more categories: b = 0.99, 95% CI [0.380, 1.593], t = 3.215, p = .002). Children with internalizing disorder who were not exposed to maltreatment did not show epigenetic ageing acceleration. There was significant enrichment of dexamethasone-responsive CpGs within the PedBE clock (OR = 4.36, p = 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.

Previous research suggests that intense, emotional pictures at fixation elicit an early posterior negativity (EPN) and a late positive potential (LPP) despite manipulations of spatial inattention and perceptual load. However, if high emotional intensity protects against such manipulations, then these manipulations should reduce emotional effects on EPN and LPP more strongly for medium than for intense emotional pictures. To test this prediction, pictures that were high negative, medium negative, or neutral were shown at fixation, and a small letter string was superimposed on the picture center. When participants attended the pictures, there were clear emotional effects on EPN and LPP. When participants attended the letter string, the emotional effects on LPP decreased; this decrease was smaller for medium than for high negative pictures. Thus, opposite of predictions, spatial inattention reduced the emotional effects more strongly for high than for medium negative pictures. As a manipulation of perceptual load, participants performed the letter task with one, three, or six relevant letters. Irrespective of load, EPN and LPP were similar for high and medium negative pictures. Our findings suggest that high negative valence does not protect EPN and LPP more strongly from effects of spatial inattention and perceptual load than does medium negative valence.

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