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

童年逆境、DNA 甲基化和抑郁风险：保护因素和发育敏感期的纵向研究

• 批准号: 10658070
• 负责人: Erin Cathleen Dunn
• 金额: $ 87.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658070
• 关键词: Adolescence; Adult; Age; Biological; Biological Process; Birth; Brain; Buffers; Candidate Disease Gene; Cell Culture Techniques; Child; Child Rearing; Child Welfare; Childhood; Communities; Consensus; DNA; DNA Methylation; Data; Data Set; Development; Disease; Environment; Epigenetic Process; Ethnic Origin; Exposure to; Family; Gene Expression; Genes; Genetic; Genome; Human; Influentials; Intervention; Life; Life Cycle Stages; Life Experience; Link; Longitudinal Studies; Measures; Mediating; Mediation; Mental Depression; Mental Health; Methods; Modeling; Modification; Molecular; Neighborhoods; Outcome; Parents; Pathway interactions; Pattern; Personal Satisfaction; Persons; Population Group; Race; Recording of previous events; Research; Research Design; Resources; Risk; Risk Factors; Risk Reduction; Schools; Shapes; Social support; Socioeconomic Status; Structure; Symptoms; Testing; Time; Umbilical Cord Blood; Variant; Work; Youth; caregiving; child depression; childhood adversity; cohort; community-level factor; depressive symptoms; diagnostic biomarker; early experience; early life adversity; epigenome; ethnic diversity; experience; experimental study; genome-wide; grandparent; in silico; in vivo; innovation; insight; methylation pattern; multidimensional data; peer; peer support; phenotypic data; population based; postnatal; prevent; promote resilience; protective effect; protective factors; racial diversity; resilience; sex; tool; young adult

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.

项目摘要。童年遭遇逆境是导致抑郁症的最大风险因素之一 在整个生命过程中，风险增加了至少两倍。尽管这些暴露显然是有害的， 人们应对逆境的方式有很大的不同；并不是所有经历过早年生活的孩子都是如此 逆境继续发展出心理健康问题。这一发现提出了一个问题：是否存在可修改的 生命早期保护免受逆境影响的因素，有助于弹性的生物过程， 并防止出现新的抑郁症状？家庭和社区层面的因素，包括产妇社会因素 支持、养育行为、祖父母参与、同伴支持和学校质量 抑郁的促进因素，即使在有逆境历史的儿童中也是如此。新兴研究 也表明DNA甲基化(DNaM)，一种研究得很好的表观遗传修饰，可能作为一种 解释这些促进因子的生物嵌入的途径。然而，之前在这一领域的研究 都是小的，横截面的，主要集中在候选基因上。因此，我们的跨学科 团队寻求通过确定dNaM在多大程度上调解或 部分解释了这些积极的生活经历对儿童至 成人期。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 儿童幸福研究(FFCWS)和总部设在英国的雅芳亲子纵向研究 (ALSPAC)。这两组人都很少包含对积极生活经历、童年的重复测量 抑郁风险的逆境、dNaM、症状和/或诊断标记物以及阳性指标 适应。利用我们团队在识别dNaM与逆境相关的敏感期方面的记录 和抑郁症，我们将利用这些数据来追求三个目标。在所有目标中，我们将对风险进行建模(即， 童年逆境暴露)和积极的生活经历，这是很少有研究做到的 在此之前。在目标1中，我们将表征积极生活经历在以下方面的时间依赖效应 从童年到成年的忧郁症。在目标2中，我们将调查积极影响的时间变化 关于dNaM模式和轨迹的生活经历。对于目标1和目标2，我们将使用两阶段结构 我们团队为高维数据开发的生命周期建模方法(SLCMA)。在《目标3》中，我们将 评估这些dNaM模式在多大程度上解释了积极生活之间的关系 使用统计中介的经验和抑郁。总之，这项研究将：1)确定可修改的 塑造dNaM和抑郁模式的积极生活经历，2)决定是否有敏感的 这些经历对塑造这些结果的影响更大的时期，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 有利于所有儿童的干预措施，并减轻逆境对受影响者的影响。