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

BIOS Consortium, Jenny van Dongen*, Fiona A Hagenbeek, Matthew Suderman, 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 Küpers, Georgia Escaramis, Silvia Alemany, Marc Jan Bonder, Mandy Meijer, Hill F IpRick 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, David L Corcoran, Richie Poulton, Jonathan Mill, Eilis Hannon, Louise Arseneault, Tellervo Korhonen, Eero Vuoksimaa, Janine F Felix, Marian J Bakermans-Kranenburg, Archie Campbell, Darina Czamara, Elisabeth Binder, Eva Corpeleijn, Juan R Gonzalez, Regina Grazuleviciene, Dennis van der Meer, Gareth E Davies, Harold Snieder, Lude Franke

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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
Number of pages15
JournalMolecular Psychiatry
DOIs
Publication statusE-pub ahead of print - 8-Jan-2021

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