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Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children

Published online by Cambridge University Press:  03 December 2020

Lorenza Dall’ Aglio ,
Jolien Rijlaarsdam ,
Rosa H. Mulder ,
Alexander Neumann ,
Janine F. Felix ,
Rianne Kok ,
Marian J. Bakermans-Kranenburg ,
Marinus H. van Ijzendoorn ,
Henning Tiemeier  and
Charlotte A.M. Cecil
Lorenza Dall’ Aglio
Affiliation:
Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Jolien Rijlaarsdam
Affiliation:
Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Rosa H. Mulder
Affiliation:
Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Alexander Neumann
Affiliation:
Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada
Janine F. Felix
Affiliation:
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Rianne Kok
Affiliation:
Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands
Marian J. Bakermans-Kranenburg
Affiliation:
Clinical Child and Family Studies, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Marinus H. van Ijzendoorn
Affiliation:
Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands Primary Care Unit School of Clinical Medicine, University of Cambridge, UK
Henning Tiemeier
Affiliation:
Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, USA
Charlotte A.M. Cecil*
Affiliation:
Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands
*
Author for correspondence: Charlotte A.M. Cecil, E-mail: c.cecil@erasmusmc.nl
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Abstract

Background

Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment.

Methods

Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses.

Results

Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10−07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4.

Conclusions

These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

Keywords

Caregiving environmentchild developmentDNA methylationepigeneticsEWASmaternal carematernal sensitivitymQTLspopulation-based sample
Type
Original Article
Information
Psychological Medicine , Volume 52 , Issue 13 , October 2022 , pp. 2481 - 2491
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Copyright
Copyright © The Author(s), 2020. Published by Cambridge University Press

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Footnotes

*

Authors contributed equally.

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