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

Kupers, 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., Allard, C., Just, A. C., Bakulski, K. M., Holloway, J. W., Everson, T. M., Xu, C-J., Huang, R-C., van der Plaat, D. A., Wielscher, M., Merid, S. K., Ullemar, V., Rezwan, F., Lahti, J., van Dongen, J., Langie, S. A. S., Richardson, T. G., Magnus, M. C., Nohr, E. A., Xu, Z., Duijts, L., Zhao, S., Zhang, W., Plusquin, M., DeMeo, D. L., Solomon, O., Heimovaara, J. H., Jima, D. D., Gao, L., Bustamante, M., Perron, P., Wright, R. O., Hertz-Picciotto, I., Zhang, H., Karagas, M. R., Gehring, U., Marsit, C. J., Beilin, L. J., Vonk, J. M., Jarvelin, M-R., Bergstrom, A., Ortqvist, A. K., Ewart, S., Villa, P. M., Moore, S. E., Willemsen, G., Standaert, A. R. L., Haberg, S. E., Sorensen, T. I. A., Taylor, J. A., Raikkonen, K., Yang, I., Kechris, K., Nawrot, T. S., Silver, M. J., Gong, Y. Y., Richiardi, L., Kogevinas, M., Litonjua, A. A., Eskenazi, B., Huen, K., Mbarek, H., Maguire, R. L., Dwyer, T., Vrijheid, M., Bouchard, L., Baccarelli, A. A., Croen, L. A., Karmaus, W., Anderson, D., de Vries, M., Sebert, S., Kere, J., Karlsson, R., Arshad, S. H., Hamalainen, E., Routledge, M. N., Boomsma, D., Feinberg, A. P., Newschaffer, C. J., Govarts, E., Moisse, M., Fallin, M. D., Melen, E., Prentice, A. M., Kajantie, E., Almqvist, C., Oken, E., Dabelea, D., Boezen, H. M., Melton, P. E., Wright, R. J., Koppelman, G. H., Trevisi, L., Hivert, M-F., Sunyer, J., Munthe-Kaas, M. C., Murphy, S. K., Corpeleijn, E., Wiemels, J., Holland, N., Herceg, Z., Binder, E. B., Smith, G. D., Jaddoe, V. W. V., Lie, R. T., Nystad, W., London, S. J., Lawlor, D. A., Relton, C. L., Snieder, H. & Felix, J. F., 23-Apr-2019, In : Nature Communications. 10, 1, 11 p., 1893.

Research output: Contribution to journalArticleAcademicpeer-review

  • Leanne K. Kupers
  • 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 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 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 Bergstrom
  • Anne K. Ortqvist
  • Susan Ewart
  • Pia M. Villa
  • Sophie E. Moore
  • Gonneke Willemsen
  • Arnout R. L. Standaert
  • Siri E. Haberg
  • Thorkild I. A. Sorensen
  • Jack A. Taylor
  • Katri Raikkonen
  • Ivana 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 Hamalainen
  • Michael N. Routledge
  • Dorret Boomsma
  • Andrew P. Feinberg
  • Craig J. Newschaffer
  • Eva Govarts
  • Matthieu Moisse
  • M. Daniele Fallin
  • Erik Melen
  • 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

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
Number of pages11
JournalNature Communications
Volume10
Issue number1
Publication statusPublished - 23-Apr-2019

    Keywords

  • MENDELIAN RANDOMIZATION, MATERNAL SMOKING, FETAL ORIGINS, CORD BLOOD, EPIGENETIC MEDIATION, GENETIC-EVIDENCE, PREGNANCY, PACKAGE, DISEASE, BIOCONDUCTOR

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