Epigenomics of being bullied: changes in DNA methylation following bullying exposure

Rosa H. Mulder; Esther Walton; Alexander Neumann; Lotte C. Houtepen; Janine F. Felix; Marian J. Bakermans-Kranenburg; Matthew Suderman; Henning Tiemeier; Marinus H. van IJzendoorn; Caroline L. Relton; Charlotte A.M. Cecil

doi:10.1080/15592294.2020.1719303

Epigenomics of being bullied: changes in DNA methylation following bullying exposure

Rosa H. Mulder, Esther Walton, Alexander Neumann, Lotte C. Houtepen, Janine F. Felix, Marian J. Bakermans-Kranenburg, Matthew Suderman, Henning Tiemeier, Marinus H. van IJzendoorn, Caroline L. Relton, Charlotte A.M. Cecil^*

^*Corresponding author for this work

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

Abstract

Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined n = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to 5-HTT and NR3C1. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (b = −2.67e-03, SE = 4.97e-04, p = 7.17e-08). This site is annotated to RAB14, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for 5-HTT and NR3C1. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation.

Original language	English
Pages (from-to)	750-764
Number of pages	15
Journal	Epigenetics
Volume	15
Issue number	6-7
Early online date	28 Jan 2020
DOIs	https://doi.org/10.1080/15592294.2020.1719303
Publication status	Published - 2 Jul 2020

Funding

RHM is supported by the Van der Gaag Grant of the Royal Netherlands Academy of Arts and Sciences and The Netherlands Organization for Scientific Research (NWA Startimpuls 400.17.602). AN is supported by a Canadian Institutes of Health Research team grant and AN and HT are supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). LCH is supported by ESRC/BBSRC Grant ES/N000382/1 for the Interpreting epigenetic signatures in studies of early life adversity project (Interstela Project). JFF has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH). This project received funding from the European Union’s Horizon 2020 research and innovation programme (733206, LIFECYCLE). MJBM is supported by the European Research Council (ERC AdG) and by the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). The work of CAMC has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 707404, and grant agreement No 848158 (EarlyCause). The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives and pharmacies in Rotterdam. The study protocol was approved by the Medical Ethical Committee of the Erasmus Medical Centre, Rotterdam. Written informed consent was obtained for all participants. The generation and management of the Illumina 450K methylation array data (EWAS data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. We thank Mr Michael Verbiest, Ms Mila Jhamai, Ms Sarah Higgins, Mr Marijn Verkerk and Dr. Lisette Stolk for their help in creating the EWAS database. We thank Dr A.Teumer for his work on the quality control and normalization scripts. The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development and the Ministry of Health, Welfare and Sport. The EWAS data was funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a grant from the National Institute of Child and Human Development (R01HD068437). We are extremely grateful to all the families who took part the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (grant number 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). This publication is the work of the authors and Dr Suderman will serve as guarantor for the ALSPAC-related contents of this paper. Analysis of the ALSPAC data was funded by UK Economic & Social Research Council grant (grant number ES/N000498/1). ARIES was funded by the BBSRC (BBI025751/1 and BB/I025263/1). Supplementary funding to generate DNA methylation data which are (or will be) included in ARIES has been obtained from the MRC, ESRC, NIH and other sources. ARIES is maintained under the auspices of the MRC Integrative Epidemiology Unit at the University of Bristol (grant numbers MC_UU_12013/2, MC_UU_12013/8 and MC_UU_12013/9).

Funders	Funder number
CAMC
Erasmus Medical Center, Rotterdam
H2020 Marie Sk?odowska
Netherlands Consortium for Healthy Aging	050-060-810
Netherlands Genomics Initiative
Netherlands Organization for Health Research and Development
National Institute of Child Health and Human Development	R01HD068437
Northwest Airlines
Wellcome Trust	102215/2/13/2
Horizon 2020 Framework Programme	707404, 848158
Canadian Institutes of Health Research
Medical Research Council
Biotechnology and Biological Sciences Research Council	BBI025751/1, BB/I025263/1, ES/N000382/1
Economic and Social Research Council	ES/N000498/1
European Research Council
University of Bristol
Ministry of Education, Culture, Sports, Science and Technology
Koninklijke Nederlandse Akademie van Wetenschappen
Erasmus Universiteit Rotterdam
Ministerie van Volksgezondheid, Welzijn en Sport
Erasmus Medisch Centrum
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.001.003, 400.17.602
Horizon 2020	733206, 633595

Keywords

ALSPAC
bullying
DNA methylation
EWAS
Generation R
Illumina 450K
longitudinal
peer victimization

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@article{358db66a46514379bab51aa898ad20fb,

title = "Epigenomics of being bullied: changes in DNA methylation following bullying exposure",

abstract = "Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined n = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to 5-HTT and NR3C1. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (b = −2.67e-03, SE = 4.97e-04, p = 7.17e-08). This site is annotated to RAB14, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for 5-HTT and NR3C1. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation.",

keywords = "ALSPAC, bullying, DNA methylation, EWAS, Generation R, Illumina 450K, longitudinal, peer victimization",

author = "Mulder, {Rosa H.} and Esther Walton and Alexander Neumann and Houtepen, {Lotte C.} and Felix, {Janine F.} and Bakermans-Kranenburg, {Marian J.} and Matthew Suderman and Henning Tiemeier and {van IJzendoorn}, {Marinus H.} and Relton, {Caroline L.} and Cecil, {Charlotte A.M.}",

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T2 - changes in DNA methylation following bullying exposure

AU - Mulder, Rosa H.

AU - Walton, Esther

AU - Neumann, Alexander

AU - Houtepen, Lotte C.

AU - Felix, Janine F.

AU - Bakermans-Kranenburg, Marian J.

AU - Suderman, Matthew

AU - Tiemeier, Henning

AU - van IJzendoorn, Marinus H.

AU - Relton, Caroline L.

AU - Cecil, Charlotte A.M.

PY - 2020/7/2

Y1 - 2020/7/2

N2 - Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined n = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to 5-HTT and NR3C1. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (b = −2.67e-03, SE = 4.97e-04, p = 7.17e-08). This site is annotated to RAB14, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for 5-HTT and NR3C1. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation.

AB - Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined n = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to 5-HTT and NR3C1. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (b = −2.67e-03, SE = 4.97e-04, p = 7.17e-08). This site is annotated to RAB14, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for 5-HTT and NR3C1. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation.

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Epigenomics of being bullied: changes in DNA methylation following bullying exposure

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