The pediatric buccal epigenetic clock identifies significant ageing acceleration in children with internalizing disorder and maltreatment exposure

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 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.

Biological aging processes underlying cognitive decline and neurodegenerative disease

“…The frequency and pattern of epigenetic changes, specifically DNA methylation at CpG sites, can be used to generate an algorithm for comparing chronological age with biological age, termed an epigenetic clock. There are currently more than seven different epigenetic clocks developed for human assessments ( 120 – 126 ) and others for mouse models ( 127 , 128 ). These differ in numbers of methylated CpGs, tissue type, and study populations.…”

Association of Pediatric Buccal Epigenetic Age Acceleration With Adverse Neonatal Brain Growth and Neurodevelopmental Outcomes Among Children Born Very Preterm With a Neonatal Infection

“…[15][16][17] Meanwhile, the advent of pediatric epigenetic clocks, such as the PedBE clock, has facilitated an enhanced understanding of brain disorders as well as behavioral and developmental conditions in the context of biological aging in children. 28,30 We extend these findings to the neurodevelopment of very preterm neonates by showing associations of the accelerated PedBE age with smaller neonatal brain volumes, slower neonatal brain growth, and adverse cognitive and language skills in early childhood. Although GA is consistently and conventionally used as the fundamental indicator of neonatal development, it may not be the optimal indicator for brain health in the NICU and after discharge, especially for extremely preterm neonates.…”

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder

“…DMR analyses in PD rendered more disease-specific DNAm changes in relation to wLE in comparison to the EWAS, as seen by the additional analysis with MDD. Most of the top associated CpGs were located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body which might contribute to age acceleration, as shown for affective disorders [ 26 , 63 ]. The specificity of the DNAm results has to be replicated in independent samples providing measurement of endocrine, vascular and cardiac function in combination with DNAm and life stress in PD.…”