DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.
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Fiona A
Hagenbeek
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Matthew
Suderman
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Peter J
Roetman
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Karen
Sugden
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Andreas G
Chiocchetti
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Khadeeja
Ismail
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Rosa H
Mulder
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Jonathan D
Hafferty
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Mark J
Adams
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Stewart W
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Alemany
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Marc
Jan Bonder
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Mandy
Meijer
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Ip
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Jansen
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Bart ML
Baselmans
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Priyanka
Parmar
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Estelle
Lowry
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Fabian
Streit
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Lea
Sirignano
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Tabea S
Send
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Josef
Frank
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Juulia
Jylhävä
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Yunzhang
Wang
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Pashupati Prasad
Mishra
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Olivier F
Colins
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David L
Corcoran
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Richie
Poulton
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Jonathan
Mill
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Eilis
Hannon
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Louise
Arseneault
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Janine F
Felix
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Marian J
Bakermans-Kranenburg
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Archie
Campbell
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Darina
Czamara
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Elisabeth
Binder
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Eva
Corpeleijn
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Juan R
Gonzalez
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Regina
Grazuleviciene
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Kristine B
Gutzkow
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Jorunn
Evandt
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Marina
Vafeiadi
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Marieke
Klein
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Dennis
van der Meer
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Lannie
Ligthart
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BIOS Consortium
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Cornelis
Kluft
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Gareth E
Davies
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Christian
Hakulinen
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Liisa
Keltikangas-Järvinen
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Barbara
Franke
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Christine M
Freitag
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Kerstin
Konrad
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Amaia
Hervas
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Aranzazu
Fernández-Rivas
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Agnes
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Olli
Raitakari
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Terho
Lehtimäki
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Robert
Vermeiren
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Timo
Strandberg
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Katri
Räikkönen
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Harold
Snieder
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Stephanie H
Witt
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Michael
Deuschle
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Nancy L
Pedersen
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Sara
Hägg
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Jordi
Sunyer
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Lude
Franke
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Jaakko
Kaprio
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Miina
Ollikainen
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Terrie E
Moffitt
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Henning
Tiemeier
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Marinus H
van IJzendoorn
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Caroline
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Martine
Vrijheid
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Sylvain
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Kathryn L
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Andrew M
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Meike
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Dorret I
Boomsma
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(2021)
DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.
Molecular psychiatry, 26 (6).
pp. 2148-2162.
ISSN 1359-4184
DOI: 10.1038/s41380-020-00987-x
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.
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