Integrative Multi-omics Analysis of Childhood Aggressive Behavior

Fiona A. Hagenbeek; Jenny van Dongen; René Pool; Peter J. Roetman; Amy C. Harms; Jouke Jan Hottenga; Cornelis Kluft; Olivier F. Colins; Catharina E.M. van Beijsterveldt; Vassilios Fanos; Erik A. Ehli; Thomas Hankemeier; Robert R.J.M. Vermeiren; Meike Bartels; Sébastien Déjean; Dorret I. Boomsma

doi:10.1007/s10519-022-10126-7

Integrative Multi-omics Analysis of Childhood Aggressive Behavior

Fiona A. Hagenbeek^*
, Jenny van Dongen
, René Pool
, Peter J. Roetman
, Amy C. Harms
, Jouke Jan Hottenga
, Cornelis Kluft
, Olivier F. Colins
, Catharina E.M. van Beijsterveldt
, Vassilios Fanos
, Erik A. Ehli
, Thomas Hankemeier
, Robert R.J.M. Vermeiren
, Meike Bartels
, Sébastien Déjean
, Dorret I. Boomsma

^*Corresponding author for this work

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

Abstract

This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

Original language	English
Pages (from-to)	101-117
Number of pages	17
Journal	Behavior Genetics
Volume	53
Issue number	2
Early online date	7 Nov 2022
DOIs	https://doi.org/10.1007/s10519-022-10126-7
Publication status	Published - Mar 2023

Bibliographical note

Funding Information:
The current work is supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” project (ACTION) and the Consortium on Individual Development (CID). ACTION received funding from the European Union Seventh Framework Program (FP7/2007–2013) under grant agreement no 602768. CID is funded through the Gravitation Program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant number 024–001-003). The Netherlands Twin Register is supported by multiple grants from the Netherlands Organizations for Scientific Research (NWO) and Medical Research (ZonMW): Netherlands Twin Registry Repository (NWO 480–15-001/674); Why some children thrive (OCW Gravity program, NWO-024.001.003); Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMw 912–10-020); Twin family database for behavior genomics studies (NWO 480–04-004); Twin research focusing on behavior (NWO 400–05-717); Longitudinal data collection from teachers of Dutch twins and their siblings (NWO 481–08-011), Twin-family-study of individual differences in school achievement (NWO-FES, 056–32-010), Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw Middelgroot 911–09-032); the Biobank-based integrative omics study (BIOS) funded by BBMRI-NL (NWO projects 184.021.007 and 184.033.111); the European Science Council (ERC) Genetics of Mental Illness (ERC Advanced, 230374, PI Boomsma); Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, USA; the Royal Netherlands Academy of Science Professor Award (PAH/6635) to D.I.B.. A research visit to the University of Toulouse (France) by F.A.H. was supported by the Faculty of Behavioural and Movement Sciences (FGB) Talent Fund (2019). J.D. is supported by the NWO-funded X-omics project (184.034.019). M.B. is supported by an ERC consolidator grant (WELL-BEING 771057, PI Bartels).

Publisher Copyright:
© 2022, The Author(s).

Funding

The current work is supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” project (ACTION) and the Consortium on Individual Development (CID). ACTION received funding from the European Union Seventh Framework Program (FP7/2007–2013) under grant agreement no 602768. CID is funded through the Gravitation Program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant number 024–001-003). The Netherlands Twin Register is supported by multiple grants from the Netherlands Organizations for Scientific Research (NWO) and Medical Research (ZonMW): Netherlands Twin Registry Repository (NWO 480–15-001/674); Why some children thrive (OCW Gravity program, NWO-024.001.003); Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMw 912–10-020); Twin family database for behavior genomics studies (NWO 480–04-004); Twin research focusing on behavior (NWO 400–05-717); Longitudinal data collection from teachers of Dutch twins and their siblings (NWO 481–08-011), Twin-family-study of individual differences in school achievement (NWO-FES, 056–32-010), Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw Middelgroot 911–09-032); the Biobank-based integrative omics study (BIOS) funded by BBMRI-NL (NWO projects 184.021.007 and 184.033.111); the European Science Council (ERC) Genetics of Mental Illness (ERC Advanced, 230374, PI Boomsma); Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, USA; the Royal Netherlands Academy of Science Professor Award (PAH/6635) to D.I.B.. A research visit to the University of Toulouse (France) by F.A.H. was supported by the Faculty of Behavioural and Movement Sciences (FGB) Talent Fund (2019). J.D. is supported by the NWO-funded X-omics project (184.034.019). M.B. is supported by an ERC consolidator grant (WELL-BEING 771057, PI Bartels).

Funders	Funder number
FGB
Seventh Framework Programme
Avera Institute for Human Genetics, Sioux Falls
European Science Council
Genetics of Mental Illness
Faculty of Behavioural and Movement Sciences
ZonMw
Dutch Ministry of Education, Culture, and Science
Medical Research
Université de Toulouse
BBMRI-NL	184.033.111, 184.021.007
Horizon 2020 Framework Programme	230374, 771057
European Commission	602768
???publication-publication-funding-organisation-not-added???	184.034.019, 024–001-003
Netherlands Twin Registry Repository	480–15-001/674, NWO-024.001.003, 912–10-020, NWO 481–08-011, NWO 480–04-004, NWO 400–05-717
National Institute of Mental Health	1RC2 MH089995
NWO-funded X-omics project	WELL-BEING 771057
Royal Netherlands Academy of Science	PAH/6635
NWO-FES	056–32-010, Middelgroot 911–09-032

UN SDGs

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

SDG 16 Peace, Justice and Strong Institutions

Keywords

Childhood aggression
DNA methylation
Genetic nurturing
Metabolomics
Multi-omics
Polygenic scores

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10.1007/s10519-022-10126-7Licence: CC BY

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Persistent link

Cite this

Hagenbeek, F. A., van Dongen, J., Pool, R., Roetman, P. J., Harms, A. C., Hottenga, J. J., Kluft, C., Colins, O. F., van Beijsterveldt, C. E. M., Fanos, V., Ehli, E. A., Hankemeier, T., Vermeiren, R. R. J. M., Bartels, M., Déjean, S., & Boomsma, D. I. (2023). Integrative Multi-omics Analysis of Childhood Aggressive Behavior. Behavior Genetics, 53(2), 101-117. https://doi.org/10.1007/s10519-022-10126-7

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abstract = "This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42\%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42\%) and independent clinical data (N = 142, cases = 45\%) ranged from 43 to 57\%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.",

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author = "Hagenbeek, \{Fiona A.\} and \{van Dongen\}, Jenny and Ren{\'e} Pool and Roetman, \{Peter J.\} and Harms, \{Amy C.\} and Hottenga, \{Jouke Jan\} and Cornelis Kluft and Colins, \{Olivier F.\} and \{van Beijsterveldt\}, \{Catharina E.M.\} and Vassilios Fanos and Ehli, \{Erik A.\} and Thomas Hankemeier and Vermeiren, \{Robert R.J.M.\} and Meike Bartels and S{\'e}bastien D{\'e}jean and Boomsma, \{Dorret I.\}",

note = "Funding Information: The current work is supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” project (ACTION) and the Consortium on Individual Development (CID). ACTION received funding from the European Union Seventh Framework Program (FP7/2007–2013) under grant agreement no 602768. CID is funded through the Gravitation Program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant number 024–001-003). The Netherlands Twin Register is supported by multiple grants from the Netherlands Organizations for Scientific Research (NWO) and Medical Research (ZonMW): Netherlands Twin Registry Repository (NWO 480–15-001/674); Why some children thrive (OCW Gravity program, NWO-024.001.003); Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMw 912–10-020); Twin family database for behavior genomics studies (NWO 480–04-004); Twin research focusing on behavior (NWO 400–05-717); Longitudinal data collection from teachers of Dutch twins and their siblings (NWO 481–08-011), Twin-family-study of individual differences in school achievement (NWO-FES, 056–32-010), Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw Middelgroot 911–09-032); the Biobank-based integrative omics study (BIOS) funded by BBMRI-NL (NWO projects 184.021.007 and 184.033.111); the European Science Council (ERC) Genetics of Mental Illness (ERC Advanced, 230374, PI Boomsma); Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, USA; the Royal Netherlands Academy of Science Professor Award (PAH/6635) to D.I.B.. A research visit to the University of Toulouse (France) by F.A.H. was supported by the Faculty of Behavioural and Movement Sciences (FGB) Talent Fund (2019). J.D. is supported by the NWO-funded X-omics project (184.034.019). M.B. is supported by an ERC consolidator grant (WELL-BEING 771057, PI Bartels). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

month = mar,

doi = "10.1007/s10519-022-10126-7",

language = "English",

volume = "53",

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Hagenbeek, FA , van Dongen, J , Pool, R, Roetman, PJ, Harms, AC, Hottenga, JJ, Kluft, C, Colins, OF, van Beijsterveldt, CEM, Fanos, V, Ehli, EA, Hankemeier, T, Vermeiren, RRJM, Bartels, M, Déjean, S & Boomsma, DI 2023, 'Integrative Multi-omics Analysis of Childhood Aggressive Behavior', Behavior Genetics, vol. 53, no. 2, pp. 101-117. https://doi.org/10.1007/s10519-022-10126-7

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AU - van Dongen, Jenny

AU - Pool, René

AU - Roetman, Peter J.

AU - Harms, Amy C.

AU - Hottenga, Jouke Jan

AU - Kluft, Cornelis

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AU - Vermeiren, Robert R.J.M.

AU - Bartels, Meike

AU - Déjean, Sébastien

AU - Boomsma, Dorret I.

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PY - 2023/3

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N2 - This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

AB - This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

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KW - DNA methylation

KW - Genetic nurturing

KW - Metabolomics

KW - Multi-omics

KW - Polygenic scores

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DO - 10.1007/s10519-022-10126-7

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JO - Behavior Genetics

JF - Behavior Genetics

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ER -

Integrative Multi-omics Analysis of Childhood Aggressive Behavior

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

Persistent URL (handle)

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Integrative multi-omics analysis of genomic, epigenomic, and metabolomic data for childhood aggressive behavior

Cite this