Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Leanne K. Küpers; Jenny van Dongen; Gonneke Willemsen; Hamdi Mbarek; Dorret I. Boomsma; Debbie A. Lawlor; Janine F. Felix; Pregnancy And Childhood Epigenetics Consortium

doi:10.1038/s41467-019-09671-3

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Leanne K. Küpers
, Jenny van Dongen
, Gonneke Willemsen
, Hamdi Mbarek
, Dorret I. Boomsma
, Debbie A. Lawlor^*
, Janine F. Felix
, Pregnancy And Childhood Epigenetics Consortium

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

Original language	English
Article number	1893
Pages (from-to)	1-11
Number of pages	11
Journal	Nature Communications
Volume	10
Early online date	23 Apr 2019
DOIs	https://doi.org/10.1038/s41467-019-09671-3
Publication status	Published - 2019

Funding

63Unit of Primary Care, Oulu University Hospital, Oulu, Finland. 64Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden. 65College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA. 66Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 67Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, UK. 68Department of Women and Children’s Health, King’s College London, London, UK. 69Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 70Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 71Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 72Department of Public Health & Primary Care, Leuven University, Leuven, Belgium. 73School of Food Sciences and Nutrition, University of Leeds, Leeds, UK. 74Department of Medical Sciences, University of Turin, Turin, Italy. 75AOU Citta della Salute e della Sceinza, CPO Piemonte, Turin, Italy. 76IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 77Center for Environmental Research and Children’s Health, School of Public Health, University of California, Berkeley, CA, USA. 78Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 79Department of Community and Family Medicine, Duke University Medical Center, Raleigh, NC, USA. 80The George Institute for Global Health, Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK. 81Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC, Canada. 82ECOGENE-21 Biocluster, Chicoutimi Hospital, Saguenay, QC, Canada. 83Laboratory of Precision Environmental Biosciences, Columbia University Mailman School of Public Health, New York, NY, USA. 84Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA. 85Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA. 86Department for Genomics of Common Diseases, School of Public Health, Imperial College London, London, UK. 87Folkhälsan Institute of Genetics, Helsinki, and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. 88Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

Funders	Funder number
National Institute of Child Health and Human Development
Medical Research Council	MC_UU_12013/2, MC_EX_MR/M01424X/1, MR/S003886/1
???publication-publication-funding-organisation-not-added???	12155
National Institute of Environmental Health Sciences	P30ES023515, R00ES023450, ZIAES049019, R01ES013744, R24ES028507, R01ES022223, R21ES028226, ZIAES049032, ZIAES049033, R24ES028522, R01ES025574, R01ES025531, R01ES021369
Economic and Social Research Council	ES/N000498/1
NIH Office of the Director	UH3OD023275, UG3OD023356
Biotechnology and Biological Sciences Research Council	BB/I025263/1
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R01HD034568
National Institute on Minority Health and Health Disparities	R01MD013299
Horizon 2020 Framework Programme	733206, 669545
National Institute of Allergy and Infectious Diseases	R01AI091905

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Cohort Studies

Netherlands Twin Register (NTR)

Access to Document

10.1038/s41467-019-09671-3

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478731

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Küpers, L. K., van Dongen, J., Willemsen, G., Mbarek, H., Boomsma, D. I., Lawlor, D. A., Felix, J. F., & Pregnancy And Childhood Epigenetics Consortium (2019). Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight. Nature Communications, 10, 1-11. Article 1893. https://doi.org/10.1038/s41467-019-09671-3

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title = "Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight",

abstract = "Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10\% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3\% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.",

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year = "2019",

doi = "10.1038/s41467-019-09671-3",

language = "English",

volume = "10",

pages = "1--11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Küpers, LK, van Dongen, J, Willemsen, G, Mbarek, H, Boomsma, DI, Lawlor, DA, Felix, JF & Pregnancy And Childhood Epigenetics Consortium 2019, 'Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight', Nature Communications, vol. 10, 1893, pp. 1-11. https://doi.org/10.1038/s41467-019-09671-3

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AU - Monnereau, Claire

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AU - Yousefi, Paul

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AU - Page, Christian M.

AU - Reese, Sarah E.

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AU - Czamara, Darina

AU - Starling, Anne P.

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AU - Breton, Carrie V.

AU - Allard, Catherine

AU - Just, Allan C.

AU - Bakulski, Kelly M.

AU - Holloway, John W.

AU - Everson, Todd M.

AU - Xu, Cheng Jian

AU - Huang, Rae Chi

AU - van der Plaat, Diana A.

AU - Wielscher, Matthias

AU - Merid, Simon Kebede

AU - Ullemar, Vilhelmina

AU - Rezwan, Faisal I.

AU - Lahti, Jari

AU - van Dongen, Jenny

AU - Langie, Sabine A.S.

AU - Richardson, Tom G.

AU - Magnus, Maria C.

AU - Nohr, Ellen A.

AU - Xu, Zongli

AU - Duijts, Liesbeth

AU - Zhao, Shanshan

AU - Zhang, Weiming

AU - Plusquin, Michelle

AU - DeMeo, Dawn L.

AU - Solomon, Olivia

AU - Heimovaara, Joosje H.

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AU - Wright, Robert O.

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AU - Moore, Sophie E.

AU - Willemsen, Gonneke

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AU - Yang, Ivana V.

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AU - Koppelman, Gerard H.

AU - Trevisi, Letizia

AU - Hivert, Marie France

AU - Sunyer, Jordi

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AU - Murphy, Susan K.

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AU - Wiemels, Joseph

AU - Holland, Nina

AU - Herceg, Zdenko

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AU - Davey Smith, George

AU - Jaddoe, Vincent W.V.

AU - Lie, Rolv T.

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AU - Lawlor, Debbie A.

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AU - Felix, Janine F.

AU - Pregnancy And Childhood Epigenetics Consortium

PY - 2019

Y1 - 2019

N2 - Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

AB - Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

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UR - https://www.scopus.com/pages/publications/85064924412#tab=citedBy

U2 - 10.1038/s41467-019-09671-3

DO - 10.1038/s41467-019-09671-3

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SN - 2041-1723

VL - 10

SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

M1 - 1893

ER -

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

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UN SDGs

Cohort Studies

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