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

Massachusetts General Hospital
Harvard Medical School
Broad Institute
University of Michigan, Ann Arbor
Erasmus MC
Princeton University
McLean Hospital
Mayo Clinic
Bristol Medical School
University of Bath, Department of Psychology
University of the West of England
Purdue University

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

10 Citations (Scopus)

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
DOIs	https://doi.org/10.1038/s44220-024-00345-8
Publication status	Published - Dec 2024

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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

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title = "DNA methylation mediates the link between adversity and depressive symptoms",

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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = dec,

doi = "10.1038/s44220-024-00345-8",

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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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AU - Lussier, Alexandre A.

AU - Smith, Brooke J.

AU - Fisher, Jonah

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.

PY - 2024/12

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N2 - 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.

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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VL - 2

SP - 1476

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JO - Nature Mental Health

JF - Nature Mental Health

IS - 12

M1 - 134

ER -

DNA methylation mediates the link between adversity and depressive symptoms

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