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.

项目总结。童年的逆境是抑郁症的一个潜在危险因素，增加了一生中患抑郁症的风险