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


Leanne K. Küpers, University of Bristol
Claire Monnereau, Erasmus MC
Gemma C. Sharp, University of Bristol
Paul Yousefi, University of Bristol
Lucas A. Salas, Geisel School of Medicine at Dartmouth
Akram Ghantous, International Agency for Research on Cancer
Christian M. Page, Norwegian Institute of Public Health
Sarah E. Reese, National Institute of Environmental Health Sciences (NIEHS)
Allen J. Wilcox, National Institute of Environmental Health Sciences (NIEHS)
Darina Czamara, Max Planck Institute of Psychiatry
Anne P. Starling, University of Colorado Anschutz Medical Campus
Alexei Novoloaca, International Agency for Research on Cancer
Samantha Lent, School of Public Health
Ritu Roy, UCSF Helen Diller Family Comprehensive Cancer Center
Cathrine Hoyo, NC State University
Carrie V. Breton, University of Southern California
Catherine Allard, Centre Hospitalier Universitaire de Sherbrooke
Allan C. Just, Icahn School of Medicine at Mount Sinai
Kelly M. Bakulski, University of Michigan, Ann ArborFollow
John W. Holloway, University of Southampton, Faculty of Medicine
Todd M. Everson, Rollins School of Public Health
Cheng Jian Xu, Beatrix Kinderziekenhuis
Rae Chi Huang, Telethon Kids Institute
Diana A. van der Plaat, Universitair Medisch Centrum Groningen
Matthias Wielscher, Medical Research Council
Simon Kebede Merid, Karolinska Institutet
Vilhelmina Ullemar, Karolinska Institutet
Faisal I. Rezwan, University of Southampton, Faculty of Medicine
Jari Lahti, Helsingin Yliopisto
Jenny van Dongen, Vrije Universiteit Amsterdam
Sabine A.S. Langie, Vlaamse Instelling voor Technologisch Onderzoek
Tom G. Richardson, University of Bristol
Maria C. Magnus, University of Bristol


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 (P Bonferroni < 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.

Publication Title

Nature Communications