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

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. 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 R. Gonzalez; Regina Grazuleviciene; Kristine B. Gutzkow; Jorunn Evandt; Marina Vafeiadi; Marieke Klein; Dennis Van Der Meer; Lannie Ligthart; Cornelis Kluft; Gareth E. Davies; Christian Hakulinen; Liisa Keltikangas-järvinen; Barbara Franke; Christine M. Freitag; Kerstin Konrad; Amaia Hervas; 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; Lude Franke; 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; Dorret I. Boomsma

doi: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

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. 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 R. Gonzalez, Regina Grazuleviciene, Kristine B. Gutzkow, Jorunn Evandt, Marina Vafeiadi, Marieke Klein, Dennis Van Der Meer, Lannie Ligthart, Cornelis Kluft, Gareth E. Davies, Christian Hakulinen, Liisa Keltikangas-järvinen, Barbara Franke, Christine M. Freitag, Kerstin Konrad, Amaia Hervas, 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, Lude Franke, 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, Dorret I. Boomsma

Research output: Contribution to Journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	2148-2162
Number of pages	15
Journal	Molecular Psychiatry
Volume	26
Issue number	6
Early online date	8 Jan 2021
DOIs	https://doi.org/10.1038/s41380-020-00987-x
Publication status	Published - Jun 2021

Funding

Acknowledgements 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. Conflict of interest The following authors declare a conflict of interest: BF received educational speaking fees from Medice. AMM has received research support from Eli Lilly, Janssen, and The Sackler Trust and speaker fees from Illumina and Janssen. CMF has received funding by the DFG, BMBF, State of Hessen, and the EU. She receives royalties for books on ASD, ADHD, and MDD. The other authors declare that they have no conflict of interest.

Funders	Funder number
ACTION
European Commission
BMBF
Eli Lilly
EU
Sackler Trust
Janssen
DFG
Horizon 2020 Framework Programme	602768, 733206
National Institute on Aging	R01AG010175, R01AG028555, R01AG032282, R01AG009453
National Institute on Alcohol Abuse and Alcoholism	R01AA012502
Seventh Framework Programme	848146
National Institute of Mental Health	R01MH062873
Economic and Social Research Council	ES/P010113/1
National Institute of Child Health and Human Development	R01HD077482
National Institute of Neurological Disorders and Stroke	U01NS047537
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK103246

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 16 Peace, Justice and Strong Institutions

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10.1038/s41380-020-00987-x

http://www.nature.com/articles/s41380-020-00987-x

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van Dongen, J., Hagenbeek, F. A., Suderman, M., Roetman, P. J., Sugden, K., Chiocchetti, A. G., Ismail, K., Mulder, R. H., Hafferty, J. D., Adams, M. J., Walker, R. M., Morris, S. W., Lahti, J., Küpers, L. K., Escaramis, G., Alemany, S., Jan Bonder, M., Meijer, M., Ip, H. F., ... Boomsma, D. I. (2021). DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan. Molecular Psychiatry, 26(6), 2148-2162. https://doi.org/10.1038/s41380-020-00987-x

@article{982e4b3d07184f4a8d54cf3776bc2d60,

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

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.",

author = "\{van Dongen\}, Jenny and Hagenbeek, \{Fiona A.\} and Matthew Suderman and Roetman, \{Peter J.\} and Karen Sugden and Chiocchetti, \{Andreas G.\} and Khadeeja Ismail and Mulder, \{Rosa H.\} and Hafferty, \{Jonathan D.\} and Adams, \{Mark J.\} and Walker, \{Rosie M.\} and Morris, \{Stewart W.\} and Jari Lahti and K{\"u}pers, \{Leanne K.\} and Georgia Escaramis and Silvia Alemany and \{Jan Bonder\}, Marc and Mandy Meijer and Ip, \{Hill F.\} and Rick Jansen and Baselmans, \{Bart M. L.\} and Priyanka Parmar and Estelle Lowry and Fabian Streit and Lea Sirignano and Send, \{Tabea S.\} and Josef Frank and Juulia Jylh{\"a}v{\"a} and Yunzhang Wang and Mishra, \{Pashupati Prasad\} and Colins, \{Olivier F.\} and Corcoran, \{David L.\} and Richie Poulton and Jonathan Mill and Eilis Hannon and Louise Arseneault and Tellervo Korhonen and Eero Vuoksimaa and Felix, \{Janine F.\} and Bakermans-kranenburg, \{Marian J.\} and Archie Campbell and Darina Czamara and Elisabeth Binder and Eva Corpeleijn and Gonzalez, \{Juan R.\} and Regina Grazuleviciene and Gutzkow, \{Kristine B.\} and Jorunn Evandt and Marina Vafeiadi and Marieke Klein and \{Van Der Meer\}, Dennis and Lannie Ligthart and Cornelis Kluft and Davies, \{Gareth E.\} and Christian Hakulinen and Liisa Keltikangas-j{\"a}rvinen and Barbara Franke and Freitag, \{Christine M.\} and Kerstin Konrad and Amaia Hervas and Aranzazu Fern{\'a}ndez-rivas and Agnes Vetro and Olli Raitakari and Terho Lehtim{\"a}ki and Robert Vermeiren and Timo Strandberg and Katri R{\"a}ikk{\"o}nen and Harold Snieder and Witt, \{Stephanie H.\} and Michael Deuschle and Pedersen, \{Nancy L.\} and Sara H{\"a}gg and Jordi Sunyer and Lude Franke and Jaakko Kaprio and Miina Ollikainen and Moffitt, \{Terrie E.\} and Henning Tiemeier and \{Van Ijzendoorn\}, \{Marinus H.\} and Caroline Relton and Martine Vrijheid and Sylvain Sebert and Marjo-riitta Jarvelin and Avshalom Caspi and Evans, \{Kathryn L.\} and Mcintosh, \{Andrew M.\} and Meike Bartels and Boomsma, \{Dorret I.\}",

year = "2021",

month = jun,

doi = "10.1038/s41380-020-00987-x",

language = "English",

volume = "26",

pages = "2148--2162",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "6",

}

van Dongen, J , Hagenbeek, FA, Suderman, M, Roetman, PJ, Sugden, K, Chiocchetti, AG, Ismail, K, Mulder, RH, Hafferty, JD, Adams, MJ, Walker, RM, Morris, SW, Lahti, J, Küpers, LK, Escaramis, G, Alemany, S, Jan Bonder, M, Meijer, M, Ip, HF, Jansen, R, Baselmans, BML, Parmar, P, Lowry, E, Streit, F, Sirignano, L, Send, TS, Frank, J, Jylhävä, J, Wang, Y, Mishra, PP, Colins, OF, Corcoran, DL, Poulton, R, Mill, J, Hannon, E, Arseneault, L, Korhonen, T, Vuoksimaa, E, Felix, JF, Bakermans-kranenburg, MJ, Campbell, A, Czamara, D, Binder, E, Corpeleijn, E, Gonzalez, JR, Grazuleviciene, R, Gutzkow, KB, Evandt, J, Vafeiadi, M, Klein, M, Van Der Meer, D, Ligthart, L, Kluft, C, Davies, GE, Hakulinen, C, Keltikangas-järvinen, L, Franke, B, Freitag, CM, Konrad, K, Hervas, A, Fernández-rivas, A, Vetro, A, Raitakari, O, Lehtimäki, T, Vermeiren, R, Strandberg, T, Räikkönen, K, Snieder, H, Witt, SH, Deuschle, M, Pedersen, NL, Hägg, S, Sunyer, J, Franke, L, Kaprio, J, Ollikainen, M, Moffitt, TE, Tiemeier, H, Van Ijzendoorn, MH, Relton, C, Vrijheid, M, Sebert, S, Jarvelin, M, Caspi, A, Evans, KL, Mcintosh, AM, Bartels, M & Boomsma, DI 2021, 'DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan', Molecular Psychiatry, vol. 26, no. 6, pp. 2148-2162. https://doi.org/10.1038/s41380-020-00987-x

TY - JOUR

T1 - DNA methylation signatures of aggression and closely related constructs

T2 - A meta-analysis of epigenome-wide studies across the lifespan

AU - van Dongen, Jenny

AU - Hagenbeek, Fiona A.

AU - Suderman, Matthew

AU - Roetman, Peter J.

AU - Sugden, Karen

AU - Chiocchetti, Andreas G.

AU - Ismail, Khadeeja

AU - Mulder, Rosa H.

AU - Hafferty, Jonathan D.

AU - Adams, Mark J.

AU - Walker, Rosie M.

AU - Morris, Stewart W.

AU - Lahti, Jari

AU - Küpers, Leanne K.

AU - Escaramis, Georgia

AU - Alemany, Silvia

AU - Jan Bonder, Marc

AU - Meijer, Mandy

AU - Ip, Hill F.

AU - Jansen, Rick

AU - Baselmans, Bart M. L.

AU - Parmar, Priyanka

AU - Lowry, Estelle

AU - Streit, Fabian

AU - Sirignano, Lea

AU - Send, Tabea S.

AU - Frank, Josef

AU - Jylhävä, Juulia

AU - Wang, Yunzhang

AU - Mishra, Pashupati Prasad

AU - Colins, Olivier F.

AU - Corcoran, David L.

AU - Poulton, Richie

AU - Mill, Jonathan

AU - Hannon, Eilis

AU - Arseneault, Louise

AU - Korhonen, Tellervo

AU - Vuoksimaa, Eero

AU - Felix, Janine F.

AU - Bakermans-kranenburg, Marian J.

AU - Campbell, Archie

AU - Czamara, Darina

AU - Binder, Elisabeth

AU - Corpeleijn, Eva

AU - Gonzalez, Juan R.

AU - Grazuleviciene, Regina

AU - Gutzkow, Kristine B.

AU - Evandt, Jorunn

AU - Vafeiadi, Marina

AU - Klein, Marieke

AU - Van Der Meer, Dennis

AU - Ligthart, Lannie

AU - Kluft, Cornelis

AU - Davies, Gareth E.

AU - Hakulinen, Christian

AU - Keltikangas-järvinen, Liisa

AU - Franke, Barbara

AU - Freitag, Christine M.

AU - Konrad, Kerstin

AU - Hervas, Amaia

AU - Fernández-rivas, Aranzazu

AU - Vetro, Agnes

AU - Raitakari, Olli

AU - Lehtimäki, Terho

AU - Vermeiren, Robert

AU - Strandberg, Timo

AU - Räikkönen, Katri

AU - Snieder, Harold

AU - Witt, Stephanie H.

AU - Deuschle, Michael

AU - Pedersen, Nancy L.

AU - Hägg, Sara

AU - Sunyer, Jordi

AU - Franke, Lude

AU - Kaprio, Jaakko

AU - Ollikainen, Miina

AU - Moffitt, Terrie E.

AU - Tiemeier, Henning

AU - Van Ijzendoorn, Marinus H.

AU - Relton, Caroline

AU - Vrijheid, Martine

AU - Sebert, Sylvain

AU - Jarvelin, Marjo-riitta

AU - Caspi, Avshalom

AU - Evans, Kathryn L.

AU - Mcintosh, Andrew M.

AU - Bartels, Meike

AU - Boomsma, Dorret I.

PY - 2021/6

Y1 - 2021/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85100450650

UR - https://www.scopus.com/pages/publications/85100450650#tab=citedBy

U2 - 10.1038/s41380-020-00987-x

DO - 10.1038/s41380-020-00987-x

M3 - Article

SN - 1359-4184

VL - 26

SP - 2148

EP - 2162

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 6

ER -

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

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