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

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 童年的不幸（例如，虐待，贫困）是抑郁症的一个潜在风险因素，增加了终身患病的风险。 这种常见的和沉重的疾病至少减少了两倍。虽然逆境和 和抑郁症的风险是有据可查的，但解释这种关系的生物学机制很差， 明白在本提案中，我们将通过检验脆弱性这一核心假设来解决这一差距。 对青少年和年轻人的抑郁症的产生，部分是通过逆境引起的影响， 表观遗传变化发生在生命的前五年的早期敏感期。敏感 时期是大脑高度可塑和经历的生命阶段（例如，逆境）可以传授 持久的影响。这一假设将在三个目标上进行前瞻性测试-在一个发现和 复制方法-使用来自两个大型出生队列的数据：（1）雅芳父母纵向研究 （2）R世代。在目标1中，我们将研究发展的 暴露于逆境的时间可以预测血液DNA甲基化（DNA m）。我们将使用创新的两个- 阶段结构生命过程统计建模方法，以调查重复暴露于 在童年中期（7岁）的DNAm上，早期生活（7岁以下）的七种不同类型的逆境。 对于每种类型的逆境，我们将研究以下理论模型，以确定哪一个或 更多的是最好的数据支持：（1）一个敏感期模型，其中存在或 没有暴露于逆境的DNA依赖于暴露的时间段;（2） 积累模型，其中暴露于逆境对DNAm的影响随着 暴露的场合，无论时间;和（3）近因模型，其中暴露的影响， DNA m上的逆境对于更近端的事件更强。在目标2中，我们将使用回归和因果关系 基于推理的调解方法和孟德尔随机化来确定 7岁时DNAm的变化可预测抑郁症的发作，并介导逆境对抑郁症的影响。 青春期抑郁症在目标3中，我们将确定DNAm对以下风险的短期与长期影响： 成年抑郁症通过检查：（a）从7岁到17岁的DNAm谱的持续性;和（B） 早期与青少年逆境对17岁DNAm和成年后发病风险相对贡献 萧条在整个过程中，我们将控制遗传因素，以解释DNAm和 萧条这项研究将确定暴露于逆境和风险的分子生物标志物， 抑郁症，并确定年龄阶段时，逆境是最有可能影响这一生物标志物。这些 研究结果将告知我们的高风险/高回报发展阶段的理解，当逆境 是最有害的，也是公共卫生投资在预防抑郁症方面最有效的时候。