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

  • Leanne K Küpers
  • , Claire Monnereau
  • , Gemma C Sharp
  • , Paul Yousefi
  • , Lucas A Salas
  • , Akram Ghantous
  • , Christian M Page
  • , Sarah E Reese
  • , Allen J Wilcox
  • , Darina Czamara
  • , Anne P Starling
  • , Alexei Novoloaca
  • , Samantha Lent
  • , Ritu Roy
  • , Cathrine Hoyo
  • , Carrie V Breton
  • , Catherine Allard
  • , Allan C Just
  • , Kelly M Bakulski
  • , John W Holloway
  • Todd M Everson, Cheng-Jian Xu, Rae-Chi Huang, Diana A van der Plaat, Matthias Wielscher, Simon Kebede Merid, Vilhelmina Ullemar, Faisal I Rezwan, Jari Lahti, Jenny van Dongen, Sabine A S Langie, Tom G Richardson, Maria C Magnus, Ellen A Nohr, Zongli Xu, Liesbeth Duijts, Shanshan Zhao, Weiming Zhang, Michelle Plusquin, Dawn L DeMeo, Olivia Solomon, Joosje H Heimovaara, Dereje D Jima, Lu Gao, Mariona Bustamante, Patrice Perron, Robert O Wright, Irva Hertz-Picciotto, Hongmei Zhang, Margaret R Karagas, Ulrike Gehring, Carmen J Marsit, Lawrence J Beilin, Judith M Vonk, Marjo-Riitta Jarvelin, Anna Bergström, Anne K Örtqvist, Susan Ewart, Pia M Villa, Sophie E Moore, Gonneke Willemsen, Arnout R L Standaert, Siri E Håberg, Thorkild I A Sørensen, Jack A Taylor, Katri Räikkönen, Ivana V Yang, Katerina Kechris, Tim S Nawrot, Matt J Silver, Yun Yun Gong, Lorenzo Richiardi, Manolis Kogevinas, Augusto A Litonjua, Brenda Eskenazi, Karen Huen, Hamdi Mbarek, Rachel L Maguire, Terence Dwyer, Martine Vrijheid, Luigi Bouchard, Andrea A Baccarelli, Lisa A Croen, Wilfried Karmaus, Denise Anderson, Maaike de Vries, Sylvain Sebert, Juha Kere, Robert Karlsson, Syed Hasan Arshad, Esa Hämäläinen, Michael N Routledge, Dorret I Boomsma, Andrew P Feinberg, Craig J Newschaffer, Eva Govarts, Matthieu Moisse, M Daniele Fallin, Erik Melén, Andrew M Prentice, Eero Kajantie, Catarina Almqvist, Emily Oken, Dana Dabelea, H Marike Boezen, Phillip E Melton, Rosalind J Wright, Gerard H Koppelman, Letizia Trevisi, Marie-France Hivert, Jordi Sunyer, Monica C Munthe-Kaas, Susan K Murphy, Eva Corpeleijn, Joseph Wiemels, Nina Holland, Zdenko Herceg, Elisabeth B Binder, George Davey Smith, Vincent W V Jaddoe, Rolv T Lie, Wenche Nystad, Stephanie J London, Debbie A Lawlor, Caroline L Relton, Harold Snieder, Janine F Felix
  • University Hospitals Bristol and Weston NHS Foundation Trust
  • Loma Linda University Medical Center
  • Dartmouth College
  • Epigenetics Group
  • Norwegian Institute of Public Health
  • National Institutes of Health
  • Max Planck Institute of Psychiatry
  • University of Colorado Anschutz Medical Campus
  • Boston University
  • North Carolina State University
  • University of Southern California
  • Université de Sherbrooke
  • Icahn School of Medicine at Mount Sinai
  • Michigan State University
  • University of Southampton
  • Emory University
  • University of Groningen
  • The University of Western Australia
  • Imperial College London
  • Karolinska Institutet
  • University of Helsinki
  • Vrije Universiteit Amsterdam
  • Flemish Institute for Technological Research
  • University of Southern Denmark
  • Wageningen University & Research
  • National Institute of Environmental Health Sciences
  • Hasselt University
  • Harvard University
  • Barcelona Institute for Global Health
  • University of California, Davis
  • University of Memphis
  • Utrecht University
  • London School of Hygiene & Tropical Medicine
  • University of Leeds
  • University of Turin
  • Amsterdam Movement Sciences
  • Oxford Brookes University
  • Columbia University
  • Nevada Division of Public and Behavioral Health
  • University of Oulu
  • Observatório de Favelas
  • Northwestern University
  • Johns Hopkins University
  • Drexel University
  • KU Leuven
  • National Institute of Health and Family Welfare
  • Duke University
  • University of California, San Francisco
  • University of California, Berkeley
  • Harvard Pilgrim Health Care
  • Massachusetts General Hospital

Research output: Contribution to journalArticlepeer-review

166 Citations (Scopus)

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 languageEnglish
Article number1893
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 23 Apr 2019
Externally publishedYes

Keywords

  • Adolescent
  • Adult
  • Birth Weight/genetics
  • Body Mass Index
  • Child
  • CpG Islands
  • DNA/genetics
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Fetal Development/genetics
  • Fetus
  • Folic Acid/blood
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Infant, Newborn
  • Male
  • Pregnancy
  • Prenatal Exposure Delayed Effects/blood
  • Smoking/adverse effects

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