Background: Exposure to adversity during childhood is estimated to at least double the risk of depression later in life. Some evidence suggests childhood adversity may have a greater impact on depression risk, if experienced during specific windows of development called sensitive periods. During these sensitive periods, there is evidence that adversity may leave behind biological memories, including changes in DNA methylation (DNAm). Here we ask if those changes play a role in the link between adversity and later adolescent depressive symptoms. Methods: We applied a method for high-dimensional mediation analysis using data from a subsample (n=627-675) of the Avon Longitudinal Study of Parents and Children. We first assessed the possibility of time-dependent relationships between seven types of childhood adversity (caregiver abuse, physical/sexual abuse, maternal psychopathology, one-adult household, family instability, financial stress, neighborhood disadvantage), measured on at least four occasions between ages 0-7 years, and adolescent depression at mean age 10.6. Specifically, we considered three types of life course hypotheses (sensitive periods, accumulation, and recency), and then evaluated which of these hypotheses had the strongest association in each adversity-adolescent depression relationship using the structured life course modeling approach (SLCMA; pronounced slick-mah). To conduct the mediation analyses, we used a combination of pruning and sure independence screening (a dimension reduction method) to reduce the number of methylated CpG sites under consideration to a viable subset for our sample size. We then applied a sparse group lasso penalized model to identify the top mediating loci from that subset using the combined strength of the coefficient measuring the relationship between the childhood adversity and a CpG site (α) and of the coefficient measuring the relationship between the CpG site and depressive symptoms (β) as a metric. Using a Monte Carlo method for assessing mediation (MCMAM), we assigned a significance level and confidence interval to each identified mediator. Results: Across all seven adversities, we identified a total of 70 CpG sites that showed evidence of mediating the relationship between adversity and adolescent depression symptoms. Of these 70 mediators, 37 were significant at the p < 0.05 level when applying the MCMAM, a method tailored to estimating the significance of SEM-derived mediation effects. These sites exhibited four different mediating patterns, differentiated by the direction of α and β. These patterns had signals that were: (1) both positive (19 loci), (2) both negative (18 loci), (3) positive α and negative β (23 loci) or (4) negative α and positive β (10 loci). Conclusion: Our results suggest that DNAm partially mediates the relationship between different types of childhood adversity and depressive symptoms in adolescence. These findings provide insight into the biological mechanisms that link childhood adversity to depression, which will ultimately help develop treatments to prevent depression in more vulnerable populations.

中文翻译：

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DNA甲基化部分介导童年逆境与青春期抑郁症状之间的关系

背景：据估计，童年时期暴露于逆境会使日后患抑郁症的风险至少增加一倍。一些证据表明，如果在称为敏感期的特定发展窗口中经历童年逆境可能对抑郁症风险产生更大的影响。在这些敏感时期，有证据表明逆境可能会留下生物记忆，包括 DNA 甲基化 (DNAm) 的变化。在这里，我们询问这些变化是否在逆境与后来的青少年抑郁症状之间的联系中起作用。方法：我们使用来自雅芳父母和儿童纵向研究的子样本 (n=627-675) 的数据应用了一种高维中介分析方法。我们首先评估了七种类型的儿童逆境（照顾者虐待、身体/性虐待、母亲精神病理学、一个成人家庭、家庭不稳定、经济压力、邻里劣势），在 0-7 岁之间至少测量了四次，以及平均年龄为 10.6 岁的青少年抑郁症。具体来说，我们考虑了三种类型的生命历程假设（敏感期、积累和新近），然后使用结构化生命历程建模方法（SLCMA；明显光滑-mah）。为了进行中介分析，我们结合使用了修剪和确定独立性筛选（一种降维方法）来将考虑中的甲基化 CpG 位点的数量减少到我们样本大小的可行子集。然后，我们应用稀疏组套索惩罚模型，使用衡量童年逆境与 CpG 位点 (α) 之间关系的系数和衡量 CpG 位点之间关系的系数的组合强度，从该子集中识别顶部中介位点和抑郁症状 (β) 作为衡量标准。使用蒙特卡罗方法评估中介 (MCMAM)，我们为每个确定的中介分配了显着性水平和置信区间。结果：在所有七种逆境中，我们确定了总共 70 个 CpG 位点，这些位点显示出调解逆境与青少年抑郁症状之间关系的证据。在这 70 个介体中，有 37 个在应用 MCMAM 时在 p < 0.05 水平上是显着的，MCMAM 是一种专门用于估计 SEM 衍生中介效应显着性的方法。这些位点表现出四种不同的中介模式，由 α 和 β 的方向区分。这些模式具有以下信号：(1) 两个阳性 (19 个基因座)，(2) 两个阴性 (18 个基因座)，(3) 阳性 α 和阴性 β (23 个基因座) 或 (4) 阴性 α 和阳性 β (10位点）。结论：我们的结果表明 DNAm 部分介导了不同类型的童年逆境与青春期抑郁症状之间的关系。这些发现提供了对将童年逆境与抑郁症联系起来的生物学机制的见解，这最终将有助于开发治疗方法来预防更脆弱人群的抑郁症。(3) 正α和负β（23个基因座）或（4）负α和正β（10个基因座）。结论：我们的结果表明 DNAm 部分介导了不同类型的童年逆境与青春期抑郁症状之间的关系。这些发现提供了对将童年逆境与抑郁症联系起来的生物学机制的见解，这最终将有助于开发治疗方法来预防更脆弱人群的抑郁症。(3) 正α和负β（23个基因座）或（4）负α和正β（10个基因座）。结论：我们的结果表明 DNAm 部分介导了不同类型的童年逆境与青春期抑郁症状之间的关系。这些发现提供了对将童年逆境与抑郁症联系起来的生物学机制的见解，这最终将有助于开发治疗方法来预防更脆弱人群的抑郁症。