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

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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.

Original languageEnglish
Pages (from-to)2481-2491
Number of pages11
JournalPsychological Medicine
Issue number13
Publication statusPublished - 3 Oct 2022

Bibliographical note

Funding Information:
We thank children and parents, midwives, general practitioners, hospitals, and pharmacies in Rotterdam for their contribution to Generation R, the Genetic Laboratory of the Department of Internal Medicine at Erasmus MC for the generation and management of the Infinium 450 K, Verbiest, Higgins, Jhamai, Dr Stolk, and Verkerk for their aid in the EWAS database creation, Dr Teumer for the contribution to quality control and normalization, and Dr Suderman for answering all our queries on the dmrff method. The Generation R study is supported by Erasmus MC, Erasmus University Rotterdam, the Rotterdam Homecare Foundation, the Municipal Health Service Rotterdam area, the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, the Netherlands Organization for Health Research and Development (ZonMw), and the Ministry of Health, Welfare and Sport. DNAm data were funded by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO), Netherlands Consortium for Healthy Aging (project 050-060-810), the National Institute of Child and Human Development (R01HD068437), and by the Department of Internal Medicine (Genetic Laboratory) at Erasmus MC. This project received funding from the European Union's Horizon 2020 program (project 733206). The authors are supported by the Dutch Ministry of Education, Culture, and Science and the NWO (project 024.001.003 for AN, HT, MJB-K, and MHvI), the Canadian Institutes of Health Research (AN), an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 for HT, LDA), an NWO VENI grant (project 91618147 for JR), the European Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (project 529051022; JFF), the European Research Council grant (ERC AdG 669249, MJB-K), the Netherlands Organization for Scientific Research Spinoza Prize (MHvI), and the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant (project 707404 and grant agreement 848158 EarlyCause Project for CAMC).

Publisher Copyright:
© The Author(s), 2020. Published by Cambridge University Press.

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