Childhood adversity, DNA methylation, and psychopathology symptoms: A longitudinal study of sensitive periods and chrono-epigenetics

项目摘要。童年的逆境是抑郁症的一个潜在风险因素，增加了一生中患抑郁症的风险。 这种常见的和沉重的疾病至少减少了两倍。虽然逆境和 抑郁症是有据可查的，但解释这种关系的机制却知之甚少。中 大脑R 01奖，我们有几个新的发现，关于如何童年逆境可能成为 生物嵌入通过DNA甲基化（DNAm）形成抑郁症风险，DNA甲基化是一种主要类型的 表观遗传修饰我们发现，DNA与逆境的联系可能不仅仅是分子上的， 逆境暴露的记录，而是可能作为一个生物媒介， 逆境到抑郁风险。我们还确定了出生后和前五个月的潜在敏感期 当逆境暴露对表观基因组产生更持久的影响时， 形成抑郁风险。然而，这些分析仅限于大多数欧洲血统的样本， 低、中度逆境暴露组仅2个时间点血DNAm。在这次更新中，我们 建立在我们以前的工作，探索这些关系，在人口为基础的纵向样本， 南非的儿童，他们是Drakenstein儿童健康研究（DCHS）的一部分。相对于我们的前任 DCHS的出生队列研究提供了一个前所未有的机会， 为了在一个由更多种族/民族多样化的儿童组成的既定群体中研究这些联系，许多 他们中的大多数人都经历过相当大的早期逆境，直接或间接地通过他们的家庭， exposure.我们将利用DCHS在早期收集的现有的重复逆境标记， 儿童期，并从1岁、3岁和5岁时收集的储存血液样本中获得表观遗传数据。与这些 丰富的纵向数据，我们将确定时间表观遗传学的遗传和社会驱动因素和结果， 这是一个新创造的术语，用来描述早期生命中表观遗传过程的时间动态。 当然了在目标1中，我们将描述基因型对特定年龄段DNA水平的影响， DNA的时间轨迹。在目标2中，我们将研究反复逆境暴露的作用 使用两阶段结构化生命过程建模方法测量5岁之前的DNAm模式 我们的跨学科团队为高维表观遗传学分析开发的。在目标3中，我们将使用 统计中介和因果推理方法（例如，孟德尔随机化），以评估 这些DNA模式在多大程度上解释了逆境时机与儿童行为之间的关系。 在8岁时出现内化症状，这是抑郁风险的最早迹象之一。总而言之， 将确定特定的遗传和社会因素塑造DNA模式，确定年龄时， 逆境最有可能影响这种生物标志物，并产生生物学见解，可能导致新的 预防抑郁症的干预战略，确保这些研究结果适用于不同的青年样本。

Project Summary. Childhood adversity is a potent risk factor for depression, increasing lifetime risk of this common and burdensome disorder by at least two-fold. While the association between adversity and depression is well documented, the mechanisms explaining this relationship are poorly understood. In a BRAINS R01 award, we made several new discoveries about how childhood adversity could become biologically embedded to shape depression risk through DNA methylation (DNAm), a major type of epigenetic modification. We showed that DNAm associations with adversity may not merely be molecular records of adversity exposure, but rather, possibly function as a biological mediator linking childhood adversity to depression risk. We also identified potential sensitive periods after birth and in the first five years of postnatal life when adversity exposure imparted more enduring effects on the epigenome and in shaping depression risk. However, these analyses were limited to mostly European-ancestry samples of children with low/moderate adversity exposure and only 2 time points of blood DNAm. In this renewal, we build on our prior work by exploring these relationships in a population-based longitudinal sample of children in South Africa, who are part of the Drakenstein Child Health Study (DCHS). Relative to our prior work and the field of epigenetics at large, the DCHS birth cohort provides an unprecedented opportunity to study these associations within an established group of more racially/ethnically diverse children, many of whom have experienced considerable early adversity directly or indirectly through their families own exposure. We will capitalize on existing, repeated adversity markers collected by the DCHS during early childhood and derive epigenetic data from stored blood samples collected at ages 1, 3, and 5. With these rich longitudinal data, we will identify the genetic and social drivers and outcomes of chrono-epigenetics, a newly coined term to describe the temporal dynamics of epigenetic processes, across the early life course. In Aim 1, we will characterize the effects of genotype on DNAm levels at specific ages and DNAm trajectories across time. In Aim 2, we will investigate the role of repeated adversity exposure measures before age 5 on DNAm patterns using a two-stage structured life-course modeling approach that our interdisciplinary team developed for high-dimensional epigenetic analyses. In Aim 3, we will use statistical mediation and causal inference approaches (e.g., Mendelian Randomization) to evaluate the extent to which these DNAm patterns explain the relationship between adversity timing and children’s internalizing symptoms at age 8, one of the earliest signs of depression risk. In sum, this renewal project will identify specific genetic and social factors shaping DNAm patterns, determine the ages when adversity is most likely to affect this biomarker, and generate biological insights that may lead to new intervention strategies to prevent depression, ensuring these findings apply to diverse samples of youth.