Open Access

Jenny van Dongen, Fiona A. Hagenbeek, Matthew Suderman, Peter J. Roetman, Karen Sugden, Andreas Geburtig-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. 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, 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 Ramon González Ruiz, Regina Grazuleviciene, Kristine B. Gutzkow, Jorunn Evandt, Marina Vafeiadi, Marieke Klein, Dennis van der Meer, Lannie Ligthart, Bastiaan Theodoor Heijmans, Peter A. C. 't Hoen, Joyce Berdina Josepha van Meurs, Lude Franke, Dorret I. Boomsma, René Pool, Jouke J. Hottenga, Marleen M. J. van Greevenbroek, Coen D. A. Stehouwer, Carla J. H. van der Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, Aaron Isaacs, André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Maarten van Iterson, Michiel van Galen, Jan Bot, Dasha V. Zhernakova, Peter van ’t Hof, Patrick Deelen, Irene Nooren, Matthijs Moed, Martijn Vermaat, René Luijk, Freerk van Dijk, Wibowo Arindrarto, Szymon M. Kielbasa, Morris A. Swertz, Erik. W. van Zwet, Peter-Bram ’t Hoen, Cornelis Kluft, Gareth E. Davies, Christian Hakulinen, Liisa Keltikangas-Järvinen, Barbara Franke, Christine M. Freitag, Kerstin Konrad, Amaia Hervás, Aranzazu Fernández-Rivas, Agnes Vetro, Olli Raitakari, Terho Lehtimäki, Robert Vermeiren, Timo Strandberg, Katri Räikkönen, Harold Snieder, Stephanie H. Witt, Michael Deuschle, Nancy L. Pedersen, Sara Hägg, Jordi Sunyer, Jaakko Kaprio, Miina Ollikainen, Terrie E. Moffitt, Henning Tiemeier, Marinus H. van IJzendoorn, Caroline Relton, Martine Vrijheid, Sylvain Sebert, Marjo-Riitta Jarvelin, Avshalom Caspi, Kathryn L. Evans, Andrew M. McIntosh, Meike Bartels

• 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.