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

项目摘要。童年时期的逆境是抑郁症最大的风险因素之一 在整个生命过程中，风险增加至少两倍。虽然这些暴露显然是有害的， 人们对逆境的反应有很大的差异;并不是所有经历过早期生活的孩子 逆境继续发展心理健康问题。这一发现提出了一个问题： 生命早期的因素，保护免受逆境的影响，有助于恢复生物过程， 并防止抑郁症的新发作家庭和社区一级的因素，包括产妇的社会地位 支持、亲职行为、祖父母参与、同侪支持与学校品质 抑郁症的促进因素，即使是在有逆境史的儿童中。新兴研究 也表明DNA甲基化（DNAm），一种被充分研究的表观遗传修饰，可能起着 途径来解释这些促进因子的生物嵌入。然而，这一领域的先前研究 一直是小规模的，跨部门的，主要集中在候选基因。因此，我们的跨学科 一个团队试图通过确定DNAm介导的程度来大大推进这些见解，或者 部分解释了这些积极的生活经历对童年抑郁风险的影响， 成年我们将在两个出生队列中研究这些关系：美国的脆弱家庭和 儿童福利研究（FFCWS）和英国雅芳家长和儿童纵向研究 （ALSPAC）。这两个队列都很少包含重复测量的积极生活经历，童年， 逆境，DNA m，抑郁症风险的症状和/或诊断标志物，以及阳性 适应利用我们团队在识别与不利因素相关的DNA敏感期方面的跟踪记录， 和抑郁症，我们将利用这些数据来实现三个目标。在所有目标中，我们将对风险进行建模（即， 童年逆境暴露）和积极的生活经验，很少有研究做过 以前在目标1中，我们将描述积极生活经历对 抑郁症从童年到成年在目标2中，我们将研究积极因素的时变影响。 DNA模式和轨迹的生活经验。对于目标1和2，我们将使用两阶段结构化 生命过程建模方法（SLCMA），我们的团队开发的高维数据。在目标3中，我们 评估这些DNA模式在多大程度上解释了积极生活与 使用统计中介的经验和抑郁症。总之，本研究将：1）确定可修改的 积极的生活经历，塑造DNA和抑郁模式，2）确定是否有敏感的 这些经验在塑造这些结果方面更有影响力的时期，以及3）产生 关于促进和保护生物机制的见解，可能导致新的靶向 这些干预措施使所有儿童受益，并减轻逆境对受影响儿童的影响。

Project Summary. Exposure to childhood adversity is one of the strongest risk factors for depression across the life course, increasing risk by at least twofold. Although these exposures are clearly harmful, there is substantial variation in how people respond to adversity; not all children who experience early-life adversity go on to develop mental health problems. This finding raises the question: Are there modifiable factors early in life that protect against the effects of adversity, contribute to resilient biological processes, and prevent new onsets of depression? Family- and community-level factors, including maternal social support, parenting behaviors, grandparent involvement, peer support, and school quality, are established promotive factors for depression, even among children with a history of adversity. Emerging research also suggests DNA methylation (DNAm), a well-studied epigenetic modification, may function as a pathway to explain the biological embedding of these promotive factors. Yet, prior studies in this field have been small, cross-sectional, and focused mostly on candidate genes. As such, our interdisciplinary team seeks to considerably advance these insights by identifying the extent to which DNAm mediates, or partially explains, the effect of these positive life experiences on risk for depression across childhood to adulthood. We will study these relationships in two birth cohorts: the US-based Fragile Families and Child Wellbeing Study (FFCWS) and the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC). Both cohorts are rare in containing repeated measures of positive life experiences, childhood adversities, DNAm, symptom and/or diagnostic markers of depression risk, and indicators of positive adaptation. Leveraging our team’s track-record of identifying adversity-linked sensitive periods for DNAm and depression, we will capitalize on these data to pursue three aims. In all aims, we will model risk (i.e., childhood adversity exposure) and positive life experiences simultaneously, which few studies have done before. In Aim 1, we will characterize the time-dependent effects of positive life experiences on depression from childhood to adulthood. In Aim 2, we will investigate the time-varying impacts of positive life experiences on DNAm patterns and trajectories. For Aims 1 and 2, we will use a two-stage structured life-course modeling approach (SLCMA) our team developed for high-dimensional data. In Aim 3, we will evaluate the extent to which these DNAm patterns explain the relationship between positive life experiences and depression using statistical mediation. In sum, this study will: 1) identify modifiable positive life experiences that shape DNAm and depression patterns, 2) determine if there are sensitive periods when these experiences are more influential in shaping these outcomes, and 3) generate insights about promotive and protective biological mechanisms that could lead to new targeted interventions that benefit all children and mitigate the effects of adversity for those who are exposed.