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, 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

*Corresponding author for this work

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Abstract

Birthweight is associated with health outcomes across the life course. DNA methylation may be an underlying mechanism in these associations. In a meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohortsin the Pregnancy And Childhood Epigenetics Consortium, DNA methylation in neonatal blood was associated with birthweight at 955 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni<1.06x10-7 6 ). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation was also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlapped with some CpGs that were previously reported to be differentially methylated in relation to smoking56/955, penrichment=1.23x10-74) and BMI in pregnancy (3/955, penrichment=1.28x10-3 10 ), but not with those related to famine or folate levels in pregnancy. Neonatal DNA methylation is associated with birthweight, with some of the differentially methylated sites overlapping with those associated with intrauterine exposure to smoking and BMI. Whether the associations that we have observed are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
Original languageEnglish
Article number1893
Number of pages11
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 23 Apr 2019

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Keywords

  • DNA methylation
  • epidemiology
  • epigenetics
  • Paediatric research

Cite this

Küpers, L. K., Monnereau, C., Sharp, G. C., Yousefi, P., Salas, L. A., Ghantous, A., Page, C. M., Reese, S. E., Wilcox, A. J., Czamara, D., Starling, A. P., Novoloaca, A., Lent, S., Roy, R., Hoyo, C., Breton, C. V., Allard, C., Just, A. C., Bakulski, K. M., ... Felix, J. F. (2019). Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight. Nature Communications, 10(1), [1893]. https://doi.org/10.1038/s41467-019-09671-3