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的危险因素，会增加一生患抑郁症的风险。 这一常见和繁重的疾病至少有两个方面。而逆境和灾难之间的联系 抑郁症是有充分证据的，但解释这种关系的机制却知之甚少。在一个 Brains R01奖，我们有了几个关于童年逆境如何变成 通过DNA甲基化(DNaM)生物嵌入形成抑郁风险，dNaM是一种主要的 表观遗传修饰。我们表明，dNaM与逆境的联系可能不仅仅是分子上的。 逆境暴露的记录，但相反，可能作为联系童年的生物中介发挥作用 逆境到抑郁的风险。我们还确定了出生后和出生后前五年的潜在敏感期。 出生后多年的生活，当逆境暴露对表观基因组和 形成抑郁的风险。然而，这些分析主要限于欧洲血统的样本。 低/中度逆境暴露且只有2个时间点的血dNaM的儿童。在这次更新中，我们 在我们先前工作的基础上，通过基于人群的纵向样本来探索这些关系 南非儿童，他们是Drakenstein儿童健康研究(DCHS)的一部分。相对于我们之前的 在整个表观遗传学领域，DCHS的出生队列提供了一个前所未有的机会 为了研究更多种族/民族多样性儿童的既定群体中的这些联系，许多 他们中的许多人通过他们的家庭直接或间接地经历了相当大的早期逆境 曝光。我们将利用疗养院在早期收集的现有的、重复的逆境标记。 并从1岁、3岁和5岁时收集的存储血液样本中获得表观遗传学数据。 丰富的纵向数据，我们将确定遗传和社会驱动因素和结果的时间表观遗传学， 一个新创造的术语，用来描述跨越早期生命的表观遗传过程的时间动力学 当然了。在目标1中，我们将表征基因对特定年龄和特定年龄的dNaM水平的影响 DNaM跨越时间的轨迹。在目标2中，我们将调查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而开发的。在目标3中，我们将使用 统计调解和因果推断方法(例如，孟德尔随机化)以评估 这些dNaM模式在多大程度上解释了逆境时机和儿童的 在8岁时内化症状，这是抑郁症风险的最早迹象之一。总而言之，这个重建项目 将确定塑造dNaM模式的特定遗传和社会因素，确定何时年龄 逆境最有可能影响这个生物标记物，并产生可能导致新的 预防抑郁症的干预策略，确保这些发现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.