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 HollowayTodd 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, Ulrike Gehring

    Research output: Contribution to journalArticleAcademicpeer-review


    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
    Pages (from-to)1893
    JournalNature Communications
    Issue number1
    Publication statusPublished - 23 Apr 2019


    • 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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