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

童年逆境、DNA 甲基化和抑郁风险：发育敏感期的纵向研究

• 批准号: 9893016
• 负责人: Erin Cathleen Dunn
• 金额: $ 53.9万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893016
• 关键词: Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Animals; Biological; Biological Markers; Birth; Blood; Brain; Candidate Disease Gene; Child; Childhood; Cross-Sectional Studies; DNA Methylation; Data; Development; Disease; Epigenetic Process; Event; Exposure to; Future; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Goals; Health Resources; Human; Human Development; Intervention; Investments; Life; Link; Long-Term Effects; Longevity; Longitudinal Studies; Mediating; Mediation; Mental Depression; Mental disorders; Modeling; Nursery Schools; Parents; Poverty; Prevention; Public Health; Randomized; Research; Risk; Risk Factors; Role; Sampling; Shapes; Statistical Models; Structure; Testing; Theoretical model; Time; Tissues; Work; Youth; adolescent-onset depression; base; child depression; childhood adversity; cohort; disorder risk; early life adversity; early onset; epigenome; experience; genome-wide; high reward; high risk; infancy; innovation; insight; lifetime risk; middle childhood; molecular marker; phenotypic data; prevent; programs; prospective; prospective test; young adult; Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Animals; Biological; Biological Markers; Birth; Blood; Brain; Candidate Disease Gene; Child; Childhood; Cross-Sectional Studies; DNA Methylation; Data; Development; Disease; Epigenetic Process; Event; Exposure to; Future; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Goals; Health Resources; Human; Human Development; Intervention; Investments; Life; Link; Long-Term Effects; Longevity; Longitudinal Studies; Mediating; Mediation; Mental Depression; Mental disorders; Modeling; Nursery Schools; Parents; Poverty; Prevention; Public Health; Randomized; Research; Risk; Risk Factors; Role; Sampling; Shapes; Statistical Models; Structure; Testing; Theoretical model; Time; Tissues; Work; Youth; adolescent-onset depression; base; child depression; childhood adversity; cohort; disorder risk; early life adversity; early onset; epigenome; experience; genome-wide; high reward; high risk; infancy; innovation; insight; lifetime risk; middle childhood; molecular marker; phenotypic data; prevent; programs; prospective; prospective test; young adult

Project Summary Childhood adversity (e.g., abuse, poverty) 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 risk is well documented, the biological mechanisms explaining this relationship are poorly understood. In this proposal, we will address this gap by testing the central hypothesis that vulnerability to adolescent- and young adult-onset depression arises, in part, via the effects of adversity-induced epigenetic changes during an early sensitive period that occurs in the first five years of life. Sensitive periods are life stages when the brain is highly plastic and experience (e.g., adversity) can impart enduring effects. This hypothesis will be prospectively tested across three aims – in a discovery and replication approach – using data from two large birth cohorts: (1) the Avon Longitudinal Study of Parents and Children and (2) Generation R. In Aim 1, we will investigate the extent to which the developmental timing of exposure to adversity predicts blood DNA methylation (DNAm). We will use an innovative two- stage structured lifecourse statistical modeling approach to investigate the role of repeated exposure to seven distinct types of adversities during early life (up to age 7) on DNAm in middle childhood (age 7). For each type of adversity, we will investigate the following theoretical models to determine which one or more are best supported by the data: (1) a sensitive period model, in which the effect of presence or absence of exposure to adversity on DNAm depends on the time period of the exposure; (2) an accumulation model, in which the effect of exposure to adversity on DNAm increases with the number of occasions exposed, regardless of timing; and (3) a recency model, in which the effect of exposure to adversity on DNAm is stronger for more proximal events. In Aim 2, we will use regression and causal inference-based mediation approaches and Mendelian randomization to determine the degree to which age 7 DNAm changes predict adolescent-onset depression and mediate the effect of adversity on adolescent depression. In Aim 3, we will determine the short- vs. longer-term effects of DNAm on risk for young-adult depression by examining: (a) the persistence of DNAm profiles from age 7 to age 17; and (b) the relative contribution of early vs. adolescent adversity on age 17 DNAm and risk for young-adult onset depression. Throughout, we will control for genetic factors shown to explain variability in DNAm and depression. This research will identify molecular biomarkers of exposure to adversity and risk for depression and determine the age stages when adversity is most likely to affect this biomarker. These findings will inform our understanding of the high-risk/high-reward stages of development when adversity is most harmful and when public health investments could be most efficacious in preventing depression.

项目摘要 儿童广告（例如虐待，贫困）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。而冒险之间的关联 抑郁症的风险已充分记录，解释这种关系的生物学机制很差 理解。在此提案中，我们将通过检验脆弱性的中心假设来解决这一差距 到青少年和年轻成人发作的抑郁症，部分原因是冒险引起的影响 在生命的头五年发生的早期敏感时期的表观遗传变化。敏感的 时期是大脑高度塑料和经验（例如，广告）可以传达的生活阶段 持久的效果。该假设将在三个目标中进行前瞻性检验 - 在发现和 复制方法 - 使用来自两个大型出生队列的数据：（1）父母的雅芳纵向研究 和儿童以及（2）一代R。在AIM 1中，我们将研究发展的程度 暴露于广告预测血液DNA甲基化（DNA）的时间。我们将使用创新的两个 阶段结构化的生命力统计建模方法，以研究反复暴露的作用 早期生命中的七种不同类型的逆境（最高7岁）的童年（7岁）。 对于每种类型的广告，我们将研究以下理论模型，以确定哪一个或 数据最好得到更多的支持：（1）敏感的时期模型，其中存在或 在DNAM上没有接触广告，取决于暴露的时间段； （2） 累积模型，其中广告对DNAM的影响随着数量的增加而增加 无论时间安排如何（3）接收模型，其中暴露于 DNAM上的逆境对于更近端的事件更为强大。在AIM 2中，我们将使用回归和因果 基于推理的调解方法和Mendelian Randomiza- 确定程度 7岁的DNAM变化预测青少年发作的抑郁症，并调解广告对 青春期抑郁症。在AIM 3中，我们将确定DNAM的短期影响与长期影响 通过检查年轻成年抑郁症：（a）从7岁到17岁的DNAM概况的持久性； （b） 早期与青少年逆境对17岁DNAM的相对贡献和年轻成年的风险 沮丧。在整个过程中，我们将控制显示的遗传因素，以解释DNAM和 沮丧。这项研究将确定暴露于广告和风险的分子生物标志物 抑郁并确定广告最有可能影响这种生物标志物的年龄阶段。这些 发现将为我们了解广告时对开发的高风险/高回报阶段的理解 最有害的是，公共卫生投资可能最有效地预防抑郁症。