DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan
Authors: van Dongen Jenny , Hagenbeek Fiona A. , Suderman Matthew , Roetman Peter J. , Sugden Karen , Chiocchetti Andreas G. , Ismail Khadeeja , Mulder Rosa H. , Hafferty Jonathan D. , Adams Mark J. , Walker Rosie M. , Morris Stewart W. , Lahti Jari , Küpers Leanne K. , Escaramis Georgia , Alemany Silvia , Jan Bonder Marc , Meijer Mandy , Ip Hill F. , Jansen Rick , Baselmans Bart M. L. , Parmar Priyanka , Lowry Estelle , Streit Fabian , Sirignano Lea , Send Tabea S. , Frank Josef , Jylhävä Juulia , Wang Yunzhang , Mishra Pashupati Prasad , Colins Olivier F. , Corcoran David L. , Poulton Richie , Mill Jonathan , Hannon Eilis , Arseneault Louise , Korhonen Tellervo , Vuoksimaa Eero , Felix Janine F. , Bakermans-Kranenburg Marian J. , Campbell Archie , Czamara Darina , Binder Elisabeth , Corpeleijn Eva , Gonzalez Juan R. , Grazuleviciene Regina , Gutzkow Kristine B. , Evandt Jorunn , Vafeiadi Marina , Klein Marieke , van der Meer Dennis , Ligthart Lannie ,   BIOS Consortium,   Management Team, Heijmans Bastiaan T. , ’t Hoen Peter A. C. , van Meurs Joyce , Jansen Rick , Franke Lude ,   Cohort collection, Boomsma Dorret I. , Pool René , van Dongen Jenny , Hottenga Jouke J. , van Greevenbroek Marleen M. J. , Stehouwer Coen D. A. , van der Kallen Carla J. H. , Schalkwijk Casper G. , Wijmenga Cisca , Franke Lude , Zhernakova Sasha , Tigchelaar Ettje F. , Slagboom P. Eline , Beekman Marian , Deelen Joris , van Heemst Diana , Veldink Jan H. , van den Berg Leonard H. , van Duijn Cornelia M. , Hofman Bert A. , Isaacs Aaron , Uitterlinden André G. ,   Data Generation, van Meurs Joyce , Jhamai P. Mila , Verbiest Michael , Suchiman H. Eka D. , Verkerk Marijn , van der Breggen Ruud , van Rooij Jeroen , Lakenberg Nico ,   Data management and computational infrastructure, Mei Hailiang , van Iterson Maarten , van Galen Michiel , Bot Jan , Zhernakova Dasha V. , Jansen Rick , van ’t Hof Peter , Deelen Patrick , Nooren Irene , ’t Hoen Peter A. C. , Heijmans Bastiaan T. , Moed Matthijs ,   Data Analysis Group, Franke Lude , Vermaat Martijn , Zhernakova Dasha V. , Luijk René , Jan Bonder Marc , van Iterson Maarten , Deelen Patrick , van Dijk Freerk , van Galen Michiel , Arindrarto Wibowo , Kielbasa Szymon M. , Swertz Morris A. , van Zwet Erik. W. , Jansen Rick , ’t Hoen Peter-Bram , Heijmans Bastiaan T. , Kluft Cornelis , Davies Gareth E. , Hakulinen Christian , Keltikangas-Järvinen Liisa , Franke Barbara , Freitag Christine M. , Konrad Kerstin , Hervas Amaia , Fernández-Rivas Aranzazu , Vetro Agnes , Raitakari Olli , Lehtimäki Terho , Vermeiren Robert , Strandberg Timo , Räikkönen Katri , Snieder Harold , Witt Stephanie H. , Deuschle Michael , Pedersen Nancy L. , Hägg Sara , Sunyer Jordi , Franke Lude , Kaprio Jaakko , Ollikainen Miina , Moffitt Terrie E. , Tiemeier Henning , van IJzendoorn Marinus H. , Relton Caroline , Vrijheid Martine , Sebert Sylvain , Jarvelin Marjo-Riitta , Caspi Avshalom , Evans Kathryn L. , McIntosh Andrew M. , Bartels Meike , Boomsma Dorret I. 
Published: January 2021

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.