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

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $539,041

## Abstract

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.

## Key facts

- **NIH application ID:** 9893016
- **Project number:** 5R01MH113930-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Erin Cathleen Dunn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,041
- **Award type:** 5
- **Project period:** 2017-07-18 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893016

## Citation

> US National Institutes of Health, RePORTER application 9893016, Childhood adversity, DNA methylation, and risk for depression: A longitudinal study of sensitive periods in development (5R01MH113930-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893016. Licensed CC0.

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