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.

中文翻译：

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儿科口腔表观遗传时钟确定了患有内化障碍和虐待暴露的儿童的显着衰老加速

背景

报告患有情感障碍或遭受虐待的儿童加速衰老的研究依赖于估计来自成人样本的表观遗传年龄的算法。这些算法在早期发育过程中对表观遗传年龄估计的有效性有限。我们在这里使用儿科口腔表观遗传 (PedBE) 时钟来预测患有和不患有内化障碍的儿童基于 DNA 甲基化的衰老偏差，并评估虐待暴露的调节作用。我们进一步进行基因集富集分析，以评估糖皮质激素信号传导对 PedBE 时钟结果的贡献。

方法

从 158 名儿童 [73 名女孩，85 名男孩；平均年龄 (SD) = 4.25 (0.8) 岁] 包括患有内化障碍和遭受虐待的儿童。基于 PedBE 时钟的 94 个 CpG 的 DNA 甲基化估计表观遗传年龄。在患有和不患有内化障碍的儿童之间对比了表观遗传年龄的残差与实际年龄的关系。虐待被编码为 3 个严重程度，并进入适度模型。全基因组地塞米松反应性 CpG 来自独立样本，并确定了这些 CpG 在 PedBE 时钟内的富集。

结果

与没有内化障碍的儿童相比，内化障碍儿童表现出显着加速表观遗传衰老（F _1,147  = 6.67，p  = .011）。虐待严重程度显着缓和了这种关联（b = 0.49, 95% CI [0.073, 0.909], t = 2.322, p  = .022）。经历过虐待的内化障碍儿童相对于没有内化障碍的儿童表现出衰老加速（1-2 类：b = 0.50, 95% CI [0.170, 0.821], t = 3.008, p = .003; 3 个或更多类别：b = 0.99, 95% CI [0.380, 1.593], t = 3.215, p = .002)。没有受到虐待的内化障碍儿童没有表现出表观遗传衰老加速。PedBE 时钟内地塞米松反应性 CpG 显着富集（OR = 4.36，p  = 1.65*10-6）。在 PedBE 时钟的 94 个 CpG 中，18 个（19%）对地塞米松有反应。

结论

使用新的 PedBE 时钟，我们表明内化障碍与儿童早期的表观遗传加速老化有关。这种关联受到虐待严重程度的缓和，部分可能是由糖皮质激素驱动的。识别虐待后加速表观遗传衰老的发展驱动因素对于设计早期有针对性的干预措施至关重要。