TY - JOUR
T1 - Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight
AU - Hannon, Eilis
AU - Schendel, Diana
AU - Ladd-Acosta, Christine
AU - Grove, Jakob
AU - Hansen, Christine Søholm
AU - Hougaard, David Michael
AU - Bresnahan, Michaeline
AU - Mors, Ole
AU - Hollegaard, Mads Vilhelm
AU - Bækvad-Hansen, Marie
AU - Hornig, Mady
AU - Mortensen, Preben Bo
AU - Børglum, Anders D.
AU - Werge, Thomas
AU - Pedersen, Marianne Giørtz
AU - Nordentoft, Merete
AU - Buxbaum, Joseph D.
AU - Fallin, M. Daniele
AU - Bybjerg-Grauholm, Jonas
AU - Reichenberg, Abraham
AU - Mill, Jonathan
N1 - Funding Information:
This study was supported by grant no. HD073978 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Neurological Disorders and Stroke; and by the Beatrice and Samuel A. Seaver Foundation. The iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) team acknowledges funding from The Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project no: 294838), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. J.M. and E.H. are supported by funding from the UK Medical Research Council (K013807).
Funding Information:
Ethics. The MINERvA study was approved by the Regional Scientific Ethics Committee in Denmark and the Danish Data Protection Agency. Data accessibility. Given the nature of the MINERvA cohort, access to data can only be provided through secured systems which comply with the current Danish and EU data standards. To comply with the study’s ethical approval, access to the raw data is only available to qualified researchers upon request. All summary statistics and analysis scripts are available directly from the authors (please contact Jonas Bybjerg-Grauholm at JOGR@ssi.dk). R scripts used to perform the quality control of these data are available on GitHub: https:// github.com/ejh243/MinervaASDEWAS.git and have been archived in Zenado: https://zenodo.org/badge/latestdoi/116149862 and scripts for the analyses reported in this manuscript are available on GitHub: https://github.com/ejh243/MinervaNeonatalEWAS.git and have been archived in Zenado: https://doi.org/10.5281/ zenodo.1303340. Authors’ contributions. E.H., J.M., A.R. and D.S. designed and coordinated the study. J.B.-G., D.M.H., M.V.H., M.B.-H. and C.S.H. led generation of DNA methylation data from dried neonatal bloodspots. E.H. led and A.R., D.S., J.M., J.B.-G., J.G., C.L.-A. and M.D.F. oversaw implementation of the data analyses. D.M.H., O.M., P.B.M., A.D.B., T.W. and M.N. are principal investigators of the iPSYCH study. E.H. and J.M. drafted the manuscript, with input from A.R., D.S., C.L.-A., J.G. and J.B.-G. All co-authors read and approved the final manuscript. Competing interests. T.W. has acted as advisor and lecturer to H. Lundbeck A/S. None of the other authors report any potential conflict of interest. Funding. This study was supported by grant no. HD073978 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Neurological Disorders and Stroke; and by the Beatrice and Samuel A. Seaver Foundation. The iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) team acknowledges funding from The Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project no: 294838), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. J.M. and E.H. are supported by funding from the UK Medical Research Council (K013807). Acknowledgements. We acknowledge iPSYCH and The Lundbeck Foundation for providing samples and funding.
Publisher Copyright:
© 2019 The Author(s) Published by the Royal Society. All rights reserved.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean ¼ 6.08 days; s.d. ¼ 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p, 1 10 27 . Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.
AB - There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean ¼ 6.08 days; s.d. ¼ 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p, 1 10 27 . Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.
KW - Birth weight
KW - DNA methylation
KW - Epigenome-wide association study
KW - Gestational age
KW - Maternal smoking
KW - Mediation analysis
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U2 - 10.1098/rstb.2018.0120
DO - 10.1098/rstb.2018.0120
M3 - Article
C2 - 30966880
AN - SCOPUS:85064163758
SN - 0962-8436
VL - 374
JO - Philosophical Transactions of the Royal Society B: Biological Sciences
JF - Philosophical Transactions of the Royal Society B: Biological Sciences
IS - 1770
M1 - 20180120
ER -