DNA methylation mediates the link between adversity and depressive symptoms

Alexandre A. Lussier; Brooke J. Smith; Jonah Fisher; Mannan Luo; Janine Cerutti; Lisa Schneper; Trey Smith; Charlotte A.M. Cecil; Janine F. Felix; Colter Mitchell; Daniel A. Notterman; Kerry J. Ressler; Daniel J. Schaid; Andrew J. Simpkin; Matthew J. Suderman; Esther Walton; Andrew D.A.C. Smith; Erin C. Dunn

doi:10.1038/s44220-024-00345-8

DNA methylation mediates the link between adversity and depressive symptoms

Alexandre A. Lussier
, Brooke J. Smith
, Jonah Fisher
, Mannan Luo
, Janine Cerutti
, Lisa Schneper
, Trey Smith
, Charlotte A.M. Cecil
, Janine F. Felix
, Colter Mitchell
, Daniel A. Notterman
, Kerry J. Ressler
, Daniel J. Schaid
, Andrew J. Simpkin
, Matthew J. Suderman
, Esther Walton
, Andrew D.A.C. Smith
, Erin C. Dunn

Harvard University
Broad Institute of MIT and Harvard
University of Michigan
Erasmus University Medical Center
Princeton University
McLean Hospital
Mayo Clinic
Maynooth University
University of Bristol
University of the West of England
Purdue University

Research output: Contribution to journal › Article › peer-review

12 Citations (SciVal)

Abstract

Experiences of childhood adversity can double the risk for depression. Although the mechanisms underlying this relationship remain unclear, DNA methylation (DNAm) has emerged as a potential pathway to explain the link between adversity and depression. We thus investigated whether epigenome-wide DNAm statistically mediates the association between childhood adversity and adolescent depressive symptoms. Specifically, we performed epigenome-wide mediation analyses to investigate the role of blood-based DNAm (age 7 years) in linking seven types of adversity (ages 0–7 years) to depressive symptoms (age 10.6 years). Primary analyses were conducted in the Avon Longitudinal Study of Parents and Children and replicated in the Future of Families and Child Wellbeing Study and Generation R Study. We identified 70 cytosine–guanine dinucleotides (CpGs) that mediated 10–73% of the correlation between adversity and depressive symptoms, with DNAm differences at 39 of these CpGs showing protective effects. Our findings suggest DNAm reflects a biological pathway linking childhood adversity to depression and a potential mechanism towards resilience.

Original language	English
Article number	134
Pages (from-to)	1476-1485
Number of pages	10
Journal	Nature Mental Health
Volume	2
Issue number	12
Early online date	2 Dec 2024
DOIs	https://doi.org/10.1038/s44220-024-00345-8
Publication status	Published - 31 Dec 2024

Data Availability Statement

All data are available by request from the ALSPAC Executive Committee for researchers who meet the criteria for access to confidential data (bristol.ac.uk/alspac/researchers/access). The FFCWS data analyzed in the current study are available with permission from the Future of Families and Childhood Wellbeing Study repository (ffcws.princeton.edu/documentation). Generation R Study data are not publicly available due to privacy or ethical restrictions. The study has an open policy in regard to collaboration with other research groups. Requests for collaboration should primarily be addressed to V. Jaddoe ([email protected]). These requests are discussed in the Generation R Study Management Team regarding their study aims, overlap with ongoing studies, logistic consequences and financial contributions.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Medicine
Psychiatry and Mental health
Neuroscience (miscellaneous)
Biological Psychiatry

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10.1038/s44220-024-00345-8

Cite this

Lussier, A. A., Smith, B. J., Fisher, J., Luo, M., Cerutti, J., Schneper, L., Smith, T., Cecil, C. A. M., Felix, J. F., Mitchell, C., Notterman, D. A., Ressler, K. J., Schaid, D. J., Simpkin, A. J., Suderman, M. J., Walton, E., Smith, A. D. A. C., & Dunn, E. C. (2024). DNA methylation mediates the link between adversity and depressive symptoms. Nature Mental Health, 2(12), 1476-1485. Article 134. https://doi.org/10.1038/s44220-024-00345-8

Lussier, AA, Smith, BJ, Fisher, J, Luo, M, Cerutti, J, Schneper, L, Smith, T, Cecil, CAM, Felix, JF, Mitchell, C, Notterman, DA, Ressler, KJ, Schaid, DJ, Simpkin, AJ, Suderman, MJ, Walton, E, Smith, ADAC & Dunn, EC 2024, 'DNA methylation mediates the link between adversity and depressive symptoms', Nature Mental Health, vol. 2, no. 12, 134, pp. 1476-1485. https://doi.org/10.1038/s44220-024-00345-8

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abstract = "Experiences of childhood adversity can double the risk for depression. Although the mechanisms underlying this relationship remain unclear, DNA methylation (DNAm) has emerged as a potential pathway to explain the link between adversity and depression. We thus investigated whether epigenome-wide DNAm statistically mediates the association between childhood adversity and adolescent depressive symptoms. Specifically, we performed epigenome-wide mediation analyses to investigate the role of blood-based DNAm (age 7 years) in linking seven types of adversity (ages 0{\textendash}7 years) to depressive symptoms (age 10.6 years). Primary analyses were conducted in the Avon Longitudinal Study of Parents and Children and replicated in the Future of Families and Child Wellbeing Study and Generation R Study. We identified 70 cytosine{\textendash}guanine dinucleotides (CpGs) that mediated 10{\textendash}73\% of the correlation between adversity and depressive symptoms, with DNAm differences at 39 of these CpGs showing protective effects. Our findings suggest DNAm reflects a biological pathway linking childhood adversity to depression and a potential mechanism towards resilience.",

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AU - Luo, Mannan

AU - Cerutti, Janine

AU - Schneper, Lisa

AU - Smith, Trey

AU - Cecil, Charlotte A.M.

AU - Felix, Janine F.

AU - Mitchell, Colter

AU - Notterman, Daniel A.

AU - Ressler, Kerry J.

AU - Schaid, Daniel J.

AU - Simpkin, Andrew J.

AU - Suderman, Matthew J.

AU - Walton, Esther

AU - Smith, Andrew D.A.C.

AU - Dunn, Erin C.

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AB - Experiences of childhood adversity can double the risk for depression. Although the mechanisms underlying this relationship remain unclear, DNA methylation (DNAm) has emerged as a potential pathway to explain the link between adversity and depression. We thus investigated whether epigenome-wide DNAm statistically mediates the association between childhood adversity and adolescent depressive symptoms. Specifically, we performed epigenome-wide mediation analyses to investigate the role of blood-based DNAm (age 7 years) in linking seven types of adversity (ages 0–7 years) to depressive symptoms (age 10.6 years). Primary analyses were conducted in the Avon Longitudinal Study of Parents and Children and replicated in the Future of Families and Child Wellbeing Study and Generation R Study. We identified 70 cytosine–guanine dinucleotides (CpGs) that mediated 10–73% of the correlation between adversity and depressive symptoms, with DNAm differences at 39 of these CpGs showing protective effects. Our findings suggest DNAm reflects a biological pathway linking childhood adversity to depression and a potential mechanism towards resilience.

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DNA methylation mediates the link between adversity and depressive symptoms

Abstract

Data Availability Statement

UN SDGs

ASJC Scopus subject areas

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