Childhood adversity, DNA methylation, and risk for depression: A longitudinal study of sensitive periods in development

项目摘要 童年的逆境(如虐待、贫穷)是抑郁症的一个潜在风险因素，增加了终生罹患抑郁症的风险。 这一常见和繁重的疾病至少有两个方面。而逆境之间的联系 抑郁症的风险已经有了很好的记录，但解释这种关系的生物学机制却很差 明白了。在这项提案中，我们将通过检验脆弱性这一中心假设来解决这一差距 对于青春期和青壮年发作的抑郁症，部分原因是逆境诱导的影响 在生命的前五年的早期敏感期发生的表观遗传学变化。敏感 经期是大脑高度可塑性的生命阶段，经历(例如，逆境)可以传递 持久的影响。这一假设将在三个目标上进行前瞻性检验--在一项发现和 复制方法-使用来自两个大型出生队列的数据：(1)雅芳父母纵向研究 以及(2)R代。在目标1中，我们将调查 暴露在逆境中的时间可以预测血液DNA甲基化(DNaM)。我们将使用创新的两个- 阶段性结构化生命过程统计建模方法研究反复接触的作用 七种不同类型的逆境在早期(至7岁)在童年中期(7岁)的dNaM上。 对于每种类型的逆境，我们将研究以下理论模型，以确定哪种或哪种 更多的数据最好支持：(1)敏感期模型，在该模型中，存在或 在dNaM上是否暴露于逆境取决于暴露的时间段； 积累模型，其中，暴露于逆境对dNaM的影响随着数量的增加而增加 暴露的场合，与时间无关；以及(3)新近模型，其中暴露于 对于更接近的事件，dNaM上的逆境更强。在目标2中，我们将使用回归和因果关系 基于推理的调解方法和孟德尔随机化来确定 7岁年龄段dNaM变化预测青春期抑郁症，并在逆境的影响中起中介作用 青春期抑郁症。在目标3中，我们将确定dNaM对以下风险的短期和长期影响 通过检查：(A)从7岁到17岁的dNaM谱的持久性；和(B) 早期逆境与青春期逆境对17岁dNaM和青壮年发病风险的相对贡献 抑郁症。在整个过程中，我们将控制遗传因素来解释dNaM和dNaM的可变性 抑郁症。这项研究将确定暴露于逆境和风险的分子生物标记物 并确定逆境最有可能影响这一生物标志物的年龄阶段。这些 研究结果将有助于我们理解当遭遇逆境时发展的高风险/高回报阶段 是最有害的，也是公共卫生投资在预防抑郁症方面最有效的时候。

Project Summary Childhood adversity (e.g., abuse, poverty) 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 risk is well documented, the biological mechanisms explaining this relationship are poorly understood. In this proposal, we will address this gap by testing the central hypothesis that vulnerability to adolescent- and young adult-onset depression arises, in part, via the effects of adversity-induced epigenetic changes during an early sensitive period that occurs in the first five years of life. Sensitive periods are life stages when the brain is highly plastic and experience (e.g., adversity) can impart enduring effects. This hypothesis will be prospectively tested across three aims – in a discovery and replication approach – using data from two large birth cohorts: (1) the Avon Longitudinal Study of Parents and Children and (2) Generation R. In Aim 1, we will investigate the extent to which the developmental timing of exposure to adversity predicts blood DNA methylation (DNAm). We will use an innovative two- stage structured lifecourse statistical modeling approach to investigate the role of repeated exposure to seven distinct types of adversities during early life (up to age 7) on DNAm in middle childhood (age 7). For each type of adversity, we will investigate the following theoretical models to determine which one or more are best supported by the data: (1) a sensitive period model, in which the effect of presence or absence of exposure to adversity on DNAm depends on the time period of the exposure; (2) an accumulation model, in which the effect of exposure to adversity on DNAm increases with the number of occasions exposed, regardless of timing; and (3) a recency model, in which the effect of exposure to adversity on DNAm is stronger for more proximal events. In Aim 2, we will use regression and causal inference-based mediation approaches and Mendelian randomization to determine the degree to which age 7 DNAm changes predict adolescent-onset depression and mediate the effect of adversity on adolescent depression. In Aim 3, we will determine the short- vs. longer-term effects of DNAm on risk for young-adult depression by examining: (a) the persistence of DNAm profiles from age 7 to age 17; and (b) the relative contribution of early vs. adolescent adversity on age 17 DNAm and risk for young-adult onset depression. Throughout, we will control for genetic factors shown to explain variability in DNAm and depression. This research will identify molecular biomarkers of exposure to adversity and risk for depression and determine the age stages when adversity is most likely to affect this biomarker. These findings will inform our understanding of the high-risk/high-reward stages of development when adversity is most harmful and when public health investments could be most efficacious in preventing depression.