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^*

^*Corresponding author for this work

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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 0–7 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 - 2 Dec 2024

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© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

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2024-12 Lussier (Nature Mental Health) - DNA methylation mediates the link between adversity and depressive symptomsFinal published version, 3.36 MBLicence: Article 25fa Dutch Copyright Act

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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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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.}",

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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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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

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