DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

Fiona A. Hagenbeek, Matthew Suderman, the Biobank-based Integrative Omics Study (BIOS) Consortium, the Biobank-based Integrative Omics Study (BIOS) Consortium, Cohort collection, Data management and computational infrastructure, Data Generation, Data Analysis Group, Jenny van Dongen*, Peter J. Roetman, Karen Sugden, Andreas G. Chiocchetti, Khadeeja Ismail, Rosa H. Mulder, Jonathan D. Hafferty, Mark J. Adams, Rosie M. Walker, Stewart W. Morris, Jari Lahti, Leanne K. KüpersGeorgia Escaramis, Silvia Alemany, Marc Jan Bonder, Mandy Meijer, Hill F. Ip, Rick Jansen, Bart M.L. Baselmans, Priyanka Parmar, Estelle Lowry, Fabian Streit, Lea Sirignano, Tabea S. Send, Josef Frank, Juulia Jylhävä, Yunzhang Wang, Pashupati Prasad Mishra, Olivier F. Colins, Janine F. Felix, Lannie Ligthart, Joyce van Meurs, Rick Jansen, Jouke J. Hottenga, Cornelia M. van Duijn, Bert A. Hofman, Aaron Isaacs, André G. Uitterlinden, Joyce van Meurs, Michael Verbiest, Marijn Verkerk, Jeroen van Rooij, Freerk van Dijk, Henning Tiemeier, Marinus H. van IJzendoorn, Meike Bartels

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Original languageEnglish
JournalMolecular Psychiatry
Publication statusPublished - 8 Jan 2021

Bibliographical note

Funding Information:
Acknowledgements This work was supported by ACTION. ACTION receives funding from the European Union Seventh Framework

Funding Information:
Conflict of interest The following authors declare a conflict of interest: BF received educational speaking fees from Medice. AMM has received research support from Eli Lilly, Janssen, and The Sackler Trust and speaker fees from Illumina and Janssen. CMF has received funding by the DFG, BMBF, State of Hessen, and the EU. She receives royalties for books on ASD, ADHD, and MDD. The other authors declare that they have no conflict of interest.

Funding Information:
Program (FP7/2007–2013) under grant agreement no 602768. Cohort-specific acknowledgements are provided in eAppendix 1.

Publisher Copyright:
© 2021, The Author(s).


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