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 童年时期的逆境是导致抑郁症的最大危险因素之一。 尽管这些暴露显然是有害的，但在整个生命过程中，风险至少增加了一倍。 人们对逆境的反应存在很大差异；并非所有经历过早年生活的孩子 这一发现提出了一个问题：逆境会导致心理健康问题吗？ 生命早期的因素可以防止逆境的影响，有助于有弹性的生物过程， 预防抑郁症和新发抑郁症的家庭和社区因素，包括母亲的社会因素？ 建立支持、养育行为、祖父母参与、同伴支持和学校质量 抑郁症的促进因素，即使是有逆境史的儿童。 还表明 DNA 甲基化 (DNAm)，一种经过充分研究的表观遗传修饰，可能起到 然而，该领域的先前研究尚未找到解释这些促进因素的生物嵌入的途径。 规模较小，具有跨学科性，并且主要关注候选基因，因此，我们的跨学科研究。 团队寻求通过确定 DNAm 介导的程度来显着推进这些见解，或者 部分解释了这些积极的生活经历对整个童年时期抑郁症风险的影响 我们将在两个出生群体中研究这些关系：美国的脆弱家庭和 儿童福祉研究 (FFCWS) 和英国雅芳家长与儿童纵向研究 （ALSPAC）这两个队列都很少包含对童年时期积极生活经历的重复测量。 逆境、DNAm、抑郁风险的症状和/或诊断标志物以及积极的指标 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）和积极的生活经历同时进行，很少有研究这样做 在目标 1 中，我们将描述积极生活经历对时间的影响。 在目标 2 中，我们将研究积极情绪随时间变化的影响。 对于目标 1 和 2，我们将使用两阶段结构。 我们的团队为高维数据开发了生命历程建模方法（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 总之，本研究将：1）确定可修改的内容。 塑造 DNAm 和抑郁模式的积极生活经历，2) 决定是否存在敏感 这些经历对塑造这些结果更有影响力的时期，以及3）产生 关于促进和保护性生物机制的见解可能会导致新的目标 使所有儿童受益并减轻逆境对受影响儿童的影响的干预措施。