Childhood adversity, DNA methylation, and psychopathology symptoms: A longitudinal study of sensitive periods and chrono-epigenetics

童年逆境、DNA 甲基化和精神病理学症状：敏感期和时间表观遗传学的纵向研究

• 批准号: 10602521
• 负责人: Erin Cathleen Dunn
• 金额: $ 65.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-18 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602521
• 关键词: Adult; Affect; Age; Award; Biological; Biological Markers; Birth; Blood; Blood Banks; Blood specimen; Brain; Candidate Disease Gene; Cell Culture Techniques; Child; Child Health; Child Mental Health; Childhood; Chronic; Coin; Cross-Sectional Studies; DNA Methylation; Data; Development; Disease; Ensure; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; European ancestry; Exposure to; Family; Functional disorder; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genotype; Health Resources; Household; Human; Individual Differences; Intervention; Investments; Life; Life Cycle Stages; Link; Longevity; Longitudinal Studies; Measures; Mediating; Mediation; Mediator; Mendelian randomization; Mental Depression; Mental Health; Mental disorders; Modeling; Modification; Molecular; Outcome; Pattern; Perinatal; Population Heterogeneity; Psychopathology; Public Health; Records; Regulation; Research; Risk; Risk Factors; Risk Reduction; Role; Sampling; Scientist; Shapes; South Africa; Structure; Symptoms; Testing; Time; Umbilical Cord Blood; Work; Youth; childhood adversity; cohort; early childhood; early life adversity; epigenome; ethnic diversity; experience; experimental study; genome-wide; high dimensionality; high risk; in silico; in vivo; insight; lifetime risk; methylation pattern; neuropsychiatric disorder; population based; postnatal; prevent; prospective; racial diversity; social; social determinants; social factors; sociodemographic factors; tool; violence exposure

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.

项目摘要 童年逆境是抑郁症的一个潜在危险因素，会增加终生患抑郁症的风险。 这种常见且繁重的疾病至少有两方面的关联。 抑郁症已有详细记录，但解释这种关系的机制却知之甚少。 BRAINS R01 奖，我们对童年逆境如何变得如此有了一些新发现 生物嵌入通过 DNA 甲基化 (DNAm) 来塑造抑郁症风险，DNA 甲基化是抑郁症的主要类型 我们发现 DNAm 与逆境的关联可能不仅仅是分子层面的。 逆境暴露的记录，而是可能充当连接童年的生物中介 我们还确定了出生后和前五个时期的逆境的潜在敏感期。 出生后的数年里，逆境暴露会对表观基因组产生更持久的影响， 然而，这些分析仅限于大多数欧洲血统的样本。 低/中度逆境暴露且只有 2 个时间点的血液 DNAm 的儿童在这次更新中，我们。 通过在基于人口的纵向样本中探索这些关系，建立在我们之前的工作的基础上 南非的儿童，他们是德拉肯斯坦儿童健康研究 (DCHS) 的一部分。 DCHS 出生队列提供了前所未有的机会 为了在一个由种族/民族更加多样化的儿童组成的既定群体中研究这些关联，许多人 他们中的许多人在早期直接或间接地通过自己的家庭经历了相当大的逆境 我们将利用 DCHS 在早期收集的现有的、重复的逆境标记。 儿童时期，并从 1、3 和 5 岁时采集的储存血液样本中获取表观遗传数据。 丰富的纵向数据，我们将确定遗传和社会驱动因素以及时间表观遗传学的结果， 一个新创造的术语，用于描述整个早期生命中表观遗传过程的时间动态 在目标 1 中，我们将描述基因型对特定年龄和年龄的 DNAm 水平的影响。 DNAm 随时间变化的轨迹 在目标 2 中，我们将研究反复遭遇逆境的作用。 使用两阶段结构化生命历程建模方法测量 5 岁之前的 DNAm 模式 我们的跨学科团队为高维表观遗传分析而开发的模型，我们将在目标 3 中使用。 统计中介和因果推理方法（例如孟德尔随机化）来评估 这些 DNAm 模式在多大程度上解释了逆境时机与儿童的关系 8 岁时内化症状，这是抑郁症风险的最早迹象之一。 将识别塑造 DNA 模式的特定遗传和社会因素，确定年龄 逆境最有可能影响这一生物标志物，并产生可能导致新的生物学见解 预防抑郁症的干预策略，这些发现适用于确保青年样本的多样化。