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: 10444309
• 负责人: Erin Cathleen Dunn
• 金额: $ 67.03万
• 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/10444309
• 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 Acute Lymphocytic Leukemia; Chronic; Coin; Cross-Sectional Studies; DNA Methylation; Data; Data Analyses; Data Store; Development; Disease; Ensure; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; European; Exposure to; Family; Functional disorder; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genotype; Health Resources; Household; Human; Individual Differences; Intervention; Investments; Lead; Life; Life Cycle Stages; Link; Longevity; Longitudinal Studies; Measures; Mediating; Mediation; Mediator of activation protein; 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; Role; Sampling; Scientist; Shapes; South Africa; Structure; Sum; Symptoms; Testing; Time; Umbilical Cord Blood; Work; Youth; base; 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 and ethnic; social; social determinants; social factors; sociodemographic factors; tool; violence exposure; 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 Acute Lymphocytic Leukemia; Chronic; Coin; Cross-Sectional Studies; DNA Methylation; Data; Data Analyses; Data Store; Development; Disease; Ensure; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; European; Exposure to; Family; Functional disorder; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genotype; Health Resources; Household; Human; Individual Differences; Intervention; Investments; Lead; Life; Life Cycle Stages; Link; Longevity; Longitudinal Studies; Measures; Mediating; Mediation; Mediator of activation protein; 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; Role; Sampling; Scientist; Shapes; South Africa; Structure; Sum; Symptoms; Testing; Time; Umbilical Cord Blood; Work; Youth; base; 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 and ethnic; 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。儿童广告是抑郁症的潜在危险因素，增加了终身风险 这种常见和朴素的疾病至少有两个倍。而冒险与 抑郁症有充分的文献记载，解释这种关系的机制知之甚少。在 大脑R01奖，我们对童年广告的变化有了一些新发现 生物学上嵌入以通过DNA甲基化（DNAM）来塑造抑郁症的风险，这是主要类型 表观遗传修饰。我们表明，DNAM与广告的关联可能不仅是分子 广告曝光的记录，而是可能功能作为生物学调解人，连接童年 对抑郁症风险的逆境。我们还确定了出生后的潜在敏感时期 当广告曝光对表观基因组和in 塑造抑郁症的风险。但是，这些分析仅限于主要是欧洲委员会样本 低/中等广告的儿童，只有2个时间点的血液。在这种续约中，我们 在我们先前的工作中建立在我们先前的工作中，通过在基于人群的纵向样本中探索这些关系 南非的儿童，他们是Drakenstein儿童健康研究（DCHS）的一部分。相对于我们的先前 DCHS出生队列的工作和表观遗传学领域，提供了前所未有的机会 在一个既定范围/种族多样化的儿童中研究这些关联，许多 在他们的家人自己的家人中直接或间接地考虑了早期广告 接触。我们将利用DCH在早期收集的现有的，重复的广告标记 从1、3和5年代收集的储存的血液样本中得出的童年并得出表观遗传数据。 丰富的纵向数据，我们将确定计时型植物的遗传和社会驱动因素和结果， 一个新创造的术语，描述了早期生命的表观遗传过程的暂时动态 课程。在AIM 1中，我们将表征基因型对特定年龄和特定年龄DNAM水平的影响 DNAM跨越时间的轨迹。在AIM 2中，我们将调查重复广告曝光的作用 使用两个阶段结构化的生活途中建模方法，在5岁之前的dnn模式上进行措施 我们的跨学科团队开发了用于高维表观遗传分析的。在AIM 3中，我们将使用 统计调解和因果推断方法（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广告时间与儿童的关系之间的关系 8岁时内部化符号，这是抑郁症风险最早的迹象之一。总之，这个更新项目 将确定特定的遗传和社会因素塑造DNAN模式，确定年龄 逆境最有可能影响这种生物标志物，并产生可能导致新的生物学见解 防止抑郁症的干预策略，确保这些发现适用于青年的潜水员样本。