Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach

Alexander Neumann*, Jean Baptiste Pingault, Janine F. Felix, Vincent W.V. Jaddoe, Henning Tiemeier, Charlotte Cecil, Esther Walton

*Corresponding author for this work

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Background: DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. An estimate of R2Methylation would provide context regarding the importance of DNA methylation explaining variance in health outcomes. We therefore estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n = 775) and Generation R (n = 1382). Results: Using information from > 470,000 autosomal probes we estimated that DNA methylation at birth explains 32% (SDCV = 0.06) of gestational age variance and 5% (SDCV = 0.02) of birth weight variance. The R2Methylation estimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations. Conclusions: The results suggest that cord blood methylation explains a moderate degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R2Methylation for these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.

Original languageEnglish
Article number53
JournalClinical Epigenetics
Issue number1
Publication statusPublished - 19 Apr 2022

Bibliographical note

Funding Information:
ALSPAC The UK Medical Research Council (MRC) and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and EW will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk ). EW was partially funded by the Bath Institute for Mathematical Innovation. EW is also funded by the European Union’s Horizon 2020 research and innovation programme (grant nº 848158) and by CLOSER, whose mission is to maximise the use, value and impact of longitudinal studies. CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2017. Its initial five year grant has since been extended to March 2021 by the ESRC (grant reference: ES/K000357/1). The funders took no role in the design, execution, analysis or interpretation of the data or in the writing up of the findings. www.closer.ac.uk . GENR The general design of the Generation R Study is made possible by financial support from Erasmus MC, University Medical Center Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw) 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). A. Neumann and H. Tiemeier 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). A. Neumann is also supported by a Canadian Institutes of Health Research team grant. The work of H. Tiemeier is further supported by a NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200). The work of CC has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement No 707404.This project received funding from the European Union’s Horizon 2020 research and innovation programme (733206, LifeCycle; 633595, DynaHEALTH; 848158, EarlyCause, 874739, LongITools)) 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 ZonMw the Netherlands no.529051023).

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