University of Oulu

van Dongen, J., Hagenbeek, F.A., Suderman, M. et al. DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan. Mol Psychiatry 26, 2148–2162 (2021). https://doi.org/10.1038/s41380-020-00987-x

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

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Author: van Dongen, Jenny1; Hagenbeek, Fiona A.1; Suderman, Matthew2,3;
Roetman, Peter J.4; Sugden, Karen5,6; Chiocchetti, Andreas G.7; Ismail, Khadeeja8; Mulder, Rosa H.9,10,11; Hafferty, Jonathan D.12; Adams, Mark J.12; Walker, Rosie M.13; Morris, Stewart W.13; Lahti, Jari14,15; Kupers, Leanne K.16; Escaramis, Georgia17,18,19; Alemany, Silvia17,20,21; Bonder, Marc Jan22; Meijer, Mandy23,24; Ip, Hill F.1; Jansen, Rick25; Baselmans, Bart M. L.1; Parmar, Priyanka26,27; Lowry, Estelle26,28; Streit, Fabian29; Sirignano, Lea29; Send, Tabea S.30; Frank, Josef29; Jylhava, Juulia31; Wang, Yunzhang31; Mishra, Pashupati Prasad32,33; Colins, Olivier F.4,34; Corcoran, David L.6; Poulton, Richie35; Mill, Jonathan36; Hannon, Eilis36; Arseneault, Louise37; Korhonen, Tellervo8; Vuoksimaa, Eero8; Felix, Janine F.11,38; Bakermans-Kranenburg, Marian J.39; Campbell, Archie13; Czamara, Darina40; Binder, Elisabeth40,41; Corpeleijn, Eva16; Gonzalez, Juan R.17,20,21; Grazuleviciene, Regina42; Gutzkow, Kristine B.43; Evandt, Jorunn43; Vafeiadi, Marina44; Klein, Marieke23,24,45; van der Meer, Dennis46,47,48; Ligthart, Lannie1; Kluft, Cornelis49; Davies, Gareth E.50; Hakulinen, Christian15; Keltikangas-Jarvinen, Liisa15; Franke, Barbara23,24,51; Freitag, Christine M.7; Konrad, Kerstin52,53,54; Hervas, Amaia55; Fernandez-Rivas, Aranzazu56; Vetro, Agnes57; Raitakari, Olli58,59,60,61; Lehtimaki, Terho32,33; Vermeiren, Robert4,62; Strandberg, Timo63; Raikkonen, Katri15; Snieder, Harold16; Witt, Stephanie H.29; Deuschle, Michael30; Pedersen, Nancy L.31; Hagg, Sara31; Sunyer, Jordi17,20,21,64; Franke, Lude22; Kaprio, Jaakko8; Ollikainen, Miina8; Moffitt, Terrie E.5,6,37,65; Tiemeier, Henning10,66; van IJzendoorn, Marinus H.67,68; Relton, Caroline2,3; Vrijheid, Martine17,20,21; Sebert, Sylvain26,27,69; Järvelin, Marjo-Riitta26,27,70; Caspi, Avshalom5,6,37,65; Evans, Kathryn L.13; McIntosh, Andrew M.12; Bartels, Meike1; Boomsma, Dorret, I1
Organizations: 1Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Dept Biol Psychol, Amsterdam, Netherlands.
2Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England.
3Univ Bristol, MRC Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England.
4Leiden Univ Med Ctr, Dept Child & Adolescent Psychiat, Curium LUMC, Oegstgeest, Netherlands.
5Duke Univ, Dept Psychol & Neurosci, Durham, NC USA.
6Duke Univ, Ctr Genom & Computat Biol, Durham, NC USA.
7Goethe Univ, Univ Hosp Frankfurt, Dept Child & Adolescent Psychiat, Psychosomat & Psychotherapy, Frankfurt, Germany.
8Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.
9Leiden Univ, Inst Educ & Child Studies, Leiden, Netherlands.
10Univ Med Ctr Rotterdam, Dept Child & Adolescent Psychiat Psychol, Erasmus MC, Rotterdam, Netherlands.
11Univ Med Ctr Rotterdam, Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.
12Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland.
13Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
14Univ Turku, Turku Inst Adv Studies, Turku, Finland.
15Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland.
16Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.
17CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain.
18Univ Barcelona, Fac Med & Hlth Sci, Dept Biomed Sci, Barcelona, Spain.
19UdG, Res Grp Stat Econometr & Hlth GRECS, Girona, Spain.
20ISGlobal, Barcelona, Spain.
21Univ Pompeu Fabra UPF, Barcelona, Spain.
22Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
23Radboud Univ Nijmegen Med Ctr, Dept Human Genet, Nijmegen, Netherlands.
24Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
25Vrije Univ Amsterdam, Dept Psychiat, Amsterdam UMC, Amsterdam, Netherlands.
26Univ Oulu, Ctr Life Course Hlth Res, POB 5000, Oulu 90014, Finland.
27Univ Oulu, Bioctr Oulu, POB 5000, Oulu 90014, Finland.
28Queens Univ Belfast, Belfast, Antrim, North Ireland.
29Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany.
30Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany.
31Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
32Tampere Univ, Fac Med & Hlth Technol, Dept Clin Chem, Fimlab Labs, Tampere 33520, Finland.
33Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Tampere 33520, Finland.
34Univ Ghent, Dept Special Needs Educ, Ghent, Belgium.
35Univ Otago, Dept Psychol, Dunedin Multidisciplinary Hlth & Dev Res Unit, Dunedin, New Zealand.
36Univ Exeter, Univ Exeter Med Sch, Exeter, Devon, England.
37Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London, England.
38Univ Med Ctr Rotterdam, Dept Pediat, Erasmus MC, Rotterdam, Netherlands.
39Vrije Univ Amsterdam, Clin Child & Family Studies, Amsterdam, Netherlands.
40Max Planck Inst Psychiat, Dept Translat Res Psychiat, Kraepelinstr 2-10, D-80804 Munich, Germany.
41Emory Univ, Dept Psychiat & Behav Sci, Sch Med, 12 Execut Pk Dr, Atlanta, GA 30329 USA.
42Vytautas Magnus Univ, Dept Environm Sci, K Donelaicio Str 58, LT-44248 Kaunas, Lithuania.
43Norwegian Inst Publ Hlth, Dept Environm Hlth, Oslo, Norway.
44Univ Crete, Dept Social Med, Iraklion, Greece.
45Univ Med Ctr Utrecht, UMC Utrecht Brain Ctr, Dept Psychiat, Utrecht, Netherlands.
46Univ Oslo, Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT, Oslo, Norway.
47Univ Oslo, Inst Clin Med, Oslo, Norway.
48Maastricht Univ, Fac Hlth Med & Life Sci, Sch Mental Hlth & Neurosci, Maastricht, Netherlands.
49Good Biomarker Sci, Leiden, Netherlands.
50Avera Inst Human Genet, 3720 W 69th St, Sioux Falls, SD 57108 USA.
51Radboud Univ Nijmegen, Dept Psychiat, Med Ctr, Nijmegen, Netherlands.
52Rhein Westfal TH Aachen, Univ Hosp, Child Neuropsychol Sect, Dept Child & Adolescent Psychiat,Psychosomat & Ps, Aachen, Germany.
53Rhein Westfal TH Aachen, JARA Brain Inst 2, Mol Neurosci & Neuroimaging INM 11, Julich, Germany.
54Res Ctr Juelich, Julich, Germany.
55Hosp Univ Mutua Terrassa, Child & Adolescent Mental Hlth Serv, Barcelona, Spain.
56Basurto Univ Hosp, Psychiat Serv, Bilbao, Spain.
57Szeged Univ, Dept Pediat & Pediat Hlth Ctr, Child & Adolescent Psychiat, Szeged, Hungary.
58Univ Turku, Ctr Populat Hlth Res, Turku, Finland.
59Turku Univ Hosp, Turku, Finland.
60Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
61Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.
62Youz, Parnassia Grp, The Hague, Netherlands.
63Helsinki Univ Cent Hosp, Geriatr, Helsinki, Finland.
64IMIM Hosp del Mar Med Res Inst, Barcelona, Spain.
65Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA.
66Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA.
67Erasmus Univ, Dept Psychol Educ & Child Studies, Rotterdam, Netherlands.
68Univ London, Dept Clin Educ & Hlth Psychol, UCL, London, England.
69Imperial Coll London, Dept Med, Sect Genom Common Dis, Hammersmith Hosp Campus,Burlington Danes Bldg, London W12 0NN, England.
70Imperial Coll London, MRC PHE Ctr Environm & Hlth, Hammersmith Hosp Campus,Burlington Danes Bldg, London W12 0NN, England.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022040827779
Language: English
Published: Springer Nature, 2021
Publish Date: 2022-04-08
Description:

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.

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Series: Molecular psychiatry
ISSN: 1359-4184
ISSN-E: 1476-5578
ISSN-L: 1359-4184
Volume: 26
Issue: 6
Pages: 2148 - 2162
DOI: 10.1038/s41380-020-00987-x
OADOI: https://oadoi.org/10.1038/s41380-020-00987-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: This work was supported by ACTION. ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. Cohort-specific acknowledgements are provided in eAppendix 1.
Copyright information: © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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