B4071 - Childhood adversity DNA methylation risk scores and risk for depression across development - 20/05/2022

B number: 
Principal applicant name: 
Alexandre Lussier | Massachusetts General Hospital (United States)
Dr. Erin C. Dunn
Title of project: 
Childhood adversity, DNA methylation risk scores, and risk for depression across development
Proposal summary: 

Childhood adversity (e.g., abuse or maltreatment, family disruption or dysfunction, poverty, etc.) is one of the most potent life experiences linked to depression, nearly doubling the risk for a first onset. Emerging evidence also suggests that the effects of adversity on depression may vary based on when in the lifespan it occurs. In other words, there may be sensitive periods when the brain is “plastic” and experiences can impart more enduring effects field. However, the biological mechanisms linking childhood adversity to long-term vulnerability for depression remain poorly understood. One possibility is that adversity reprograms the epigenome through DNA methylation (DNAm), epigenetic modifications that do not change the sequence of the genome, but can alter gene expression. Recent evidence also suggests that DNAm risk scores (MRS) generated from large-scale studies of early-life exposures and/or mental outcomes may help predict and interpret risk for depression and other mental disorders.

To this end, we recently completed the largest analysis of time-varying childhood adversity and genome-wide DNAm in childhood, analyzing the impact of five types of adversity across seven longitudinal birth cohorts (N=2,347-3,279). Through these analyses, we identified distinct epigenetic signatures for five types of childhood adversity, as well as further evidence of sensitive periods for the effects of adversity on DNAm. However, it remains unknown whether DNAm risk scores generated from these data can accurately explain and predict depression risk across development.

As such, we seek to extend this research, which included data from the ALSPAC cohort, to further investigate the relationship between childhood adversity, DNAm, and depressive symptom trajectories across development. The central hypothesis we will test is that DNA methylation patterns linked to childhood adversity can be used as predictors of both prior exposures to adversity and future depressive outcomes, with measurable effects on depressive symptom trajectories.

Impact of research: 
By testing our central hypothesis, we will determine whether composite measures of childhood adversity can be identified through epigenetic alterations and whether these biological measures can predict the onset and severity of psychopathology. As the first longitudinal investigation of DNA methylation risk scores for childhood adversity and depression, this research the stage for a broader research program aimed at determining how epigenetic mechanisms can be used to predict and interpret risk for mental illness across the life course. Importantly, this work will help identify the molecular mechanisms that drive risk for depression across development, as well as delineate the periods when childhood adversity and DNA methylation have greater effects on depression risk, which will help guide optimally-timed interventions to reduce the burden of depression. Such efforts will help target prevention and treatment efforts to people who are at higher risk for mental illness and ultimately, will help improve the overall well-being of youth and adults affected by depression.
Date proposal received: 
Friday, 13 May, 2022
Date proposal approved: 
Friday, 20 May, 2022
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Computer simulations/modelling/algorithms, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Childhood - childcare, childhood adversity, Environment - enviromental exposure, pollution, Epigenetics, Genetics