Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis

Mannan Luo, Alan J Meehan, Esther Walton, Stefan Röder, Gunda Herberth, Ana C Zenclussen, Marta Cosín-Tomás, Jordi Sunyer, Rosa H Mulder, Andrea P Cortes Hidalgo, Marian J Bakermans-Kranenburg, Janine F Felix, Caroline Relton, Matthew Suderman, Irene Pappa, Rianne Kok, Henning Tiemeier, Marinus H van IJzendoorn, Edward D Barker, Charlotte A M Cecil

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.

Original languageEnglish
Pages (from-to)228-241
Number of pages14
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume186
Issue number4
Early online date25 Jun 2021
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.

Funding

The UK Medical Research Council (MRC) and Wellcome Trust (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 ). Analysis of ALSPAC data was funded by the UK Economic and Social Research Council (ESRC; ES/N000498/1). ARIES was funded by the Biotechnology and Biological Sciences Research Council (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, National Institutes of Health, and other sources. ARIES is maintained under the auspices of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/4 and MC_UU_00011/5). The ALSPAC methylation component of this article was supported by a Eunice Kennedy Shriver National Institute of Child and Human Development grant to EDB (R01HD068437) with further funding from the ESRC (ES/R005516/1). AJM was supported by the ESRC (ES/J500057/1) and National University of Ireland. This publication is the work of the authors, and EDB and CAMC serve as guarantors for the contents of this article. Core funding for the LINA study is provided by the Helmholtz Center for Environmental Research—UFZ / Department of Environmental Immunology, with methylation analysis supported by the German Cancer Research Centre—DKFZ. LINA: The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center Rotterdam, 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 Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050‐060‐810), funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and a grant from the National Institute of Child and Human Development (R01HD068437). This project received funding from the European Union's Horizon 2020 research and innovation program (733,206, LifeCycle; 848,158, EarlyCause) and from the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, ZonMw the Netherlands no.529051022 and PREcisE project no. P75416). CAMC has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska‐Curie grant agreement No 707404. CAMC and EW are supported by grant agreement No 848158 (EarlyCause). ML is supported by the scholarship from the China Scholarship Council (201706990036). MHvIJ and MJB‐K are supported 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). MJB‐K was supported by the European Research Council (ERC AdG 669,249). MHvIJ and APCH are also supported by a Spinoza Award of the Netherlands Organization for Scientific Research to MHvIJ. The epigenetic studies in INMA were mainly funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, CP18/00018), Spanish Ministry of Health (FIS‐PI04/1436, FIS‐PI08/1151 including FEDER funds, FIS‐PI11/00610, FIS‐FEDER‐PI06/0867, FIS‐FEDER‐PI03‐1615), Generalitat de Catalunya‐CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357‐MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479‐BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn). MCT is funded by a Juan de la Cierva—Formación Postdoctoral Contract awarded by Ministry of Science and Innovation (FJC2018‐036335‐I). The 4, 7, and 11 year follow‐up visits was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds; PI15/00118 incl. FEDER funds; CP16/00128 incl. FEDER funds; PI16/00118 incl. FEDER funds; PI16/00261 incl. FEDER funds; PI18/00547 incl. FEDER funds), CIBERESP, Generalitat de Catalunya‐CIRIT 1999SGR 00241, Generalitat de Catalunya‐AGAUR (2009 SGR 501, 2014 SGR 822), Fundació La marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012‐32991 incl. FEDER funds), Agence Nationale de Securite Sanitaire de l'Alimentation de l'Environnement et du Travail (1262C0010; EST‐2016 RF‐21), EU Commission (261357, 308333, 603794 and 634453). We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019‐2023” Program (CEX2018‐000806‐S), and support from the Generalitat de Catalunya through the CERCA Program. INMA: Agence Nationale de Securite Sanitaire de l'Alimentation de l'Environnement et du Travail, Grant/Award Number: 1262C0010; Agència de Gestió d'Ajuts Universitaris i de Recerca, Grant/Award Numbers: 2009 SGR 501, 2014 SGR 822; China Scholarship Council, Grant/Award Number: 201706990036; Comissió Interdepartamental de Recerca i Innovació Tecnològica, Grant/Award Number: 1999SGR 00241; Deutsches Krebsforschungszentrum; Economic and Social Research Council, Grant/Award Numbers: ES/J500057/1, ES/R005516/1; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant/Award Number: R01HD068437; European Commission, Grant/Award Numbers: 261357, 308333, 603794, 634453; Fundació la Marató de TV3, Grant/Award Number: 090430; H2020 European Research Council, Grant/Award Numbers: 268479, 669249; H2020 Marie Skłodowska‐Curie Actions, Grant/Award Numbers: 707404, 848158; Helmholtz‐Zentrum für Umweltforschung; Instituto de Salud Carlos III, Grant/Award Numbers: CB06/02/0041, CP13/00054, CP16/00128, CP18/00018, G03/176, PI041436, PI081151, PI12/01890, PI15/00118, PI16/00118, PI16/00261, PI18/00547; Medical Research Council, Grant/Award Number: MC_UU_00011/5; Ministerio de Ciencia e Innovación, Grant/Award Number: FJC2018‐036335‐I; National University of Ireland; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: 024‐001‐003, 050‐060‐810; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: SAF2012‐32991; Spanish Ministry of Health, Grant/Award Numbers: FIS‐FEDER‐PI03‐1615, FIS‐FEDER‐PI06/0867, FIS‐PI04/1436, FIS‐PI08/1151, FIS‐PI11/00610 Funding information

FundersFunder number
CIBERESP
Centro de Excelencia Severo Ochoa 2019‐2023
Erasmus Medical Center Rotterdam
Generalitat de Catalunya‐AGAUR
Generalitat de Catalunya‐CIRIT
Helmholtz Center for Environmental Research
Netherlands Consortium for Healthy Aging
Netherlands Genomics Initiative
Netherlands Organization for Health Research and Development
Spanish Ministry of HealthFIS‐PI04/1436, FIS‐PI11/00610, FIS‐PI08/1151, FIS‐FEDER‐PI03‐1615, FIS‐FEDER‐PI06/0867
Spanish Ministry of Science and Innovation and State Research Agency
National Institute of Child Health and Human DevelopmentR01HD068437
Deutsches Krebsforschungszentrum
Fundació la Marató de TV3090430
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National University of Ireland
H2020 European Research Council268479, 669249
H2020 Marie Skłodowska-Curie Actions707404
Joint Programming Initiative on Antimicrobial Resistance
Medical Research CouncilMC_UU_00011/5
Biotechnology and Biological Sciences Research CouncilBBI025751/1, BB/I025263/1
Economic and Social Research CouncilES/J500057/1, ES/N000498/1, ES/R005516/1
European Commission634453, 261357, 603794, 308333
European Research Council
Economic Development Board - Singapore
Ministry of Education, Culture, Sports, Science and Technology024.001.003
ZonMw529051022, P75416, 848158
Erasmus Universiteit Rotterdam
Generalitat de Catalunya
Ministerie van Volksgezondheid, Welzijn en Sport
Agència de Gestió d'Ajuts Universitaris i de Recerca2009 SGR 501, 2014 SGR 822
Erasmus Medisch Centrum
Nederlandse Organisatie voor Wetenschappelijk Onderzoek024‐001‐003, 050‐060‐810
Ministerio de Economía y CompetitividadSAF2012‐32991
China Scholarship Council201706990036
Instituto de Salud Carlos IIIPI041436, PI081151, PI16/00118, CB06/02/0041, G03/176, CP13/00054, CP16/00128, PI12/01890, PI15/00118, PI16/00261, PI18/00547, CP18/00018, INMA G03/176
Helmholtz-Zentrum für Umweltforschung
Ministerio de Ciencia e InnovaciónFJC2018‐036335‐I
Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travailEST‐2016 RF‐21, 1262C0010
Horizon 2020733,206
Comissió Interdepartamental de Recerca i Innovació Tecnològica1999SGR 00241

    Keywords

    • Adolescent
    • Altruism
    • Birth Cohort
    • Case-Control Studies
    • Child
    • Child, Preschool
    • Cohort Studies
    • Cordocentesis/methods
    • CpG Islands/genetics
    • DNA Methylation/genetics
    • Epigenesis, Genetic/genetics
    • Epigenome/genetics
    • Epigenomics/methods
    • Female
    • Fetal Blood/metabolism
    • Genome-Wide Association Study/methods
    • Humans
    • Infant, Newborn/metabolism
    • Male

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