Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
Authors: Küpers Leanne K. , Monnereau Claire , Sharp Gemma C. , Yousefi Paul , Salas Lucas A. , Ghantous Akram , Page Christian M. , Reese Sarah E. , Wilcox Allen J. , Czamara Darina , Starling Anne P. , Novoloaca Alexei , Lent Samantha , Roy Ritu , Hoyo Cathrine , Breton Carrie V. , Allard Catherine , Just Allan C. , Bakulski Kelly M. , Holloway John W. , Everson Todd M. , Xu Cheng-Jian , Huang Rae-Chi , van der Plaat Diana A. , Wielscher Matthias , Merid Simon Kebede , Ullemar Vilhelmina , Rezwan Faisal I. , Lahti Jari , van Dongen Jenny , Langie Sabine A. S. , Richardson Tom G. , Magnus Maria C. , Nohr Ellen A. , Xu Zongli , Duijts Liesbeth , Zhao Shanshan , Zhang Weiming , Plusquin Michelle , DeMeo Dawn L. , Solomon Olivia , Heimovaara Joosje H. , Jima Dereje D. , Gao Lu , Bustamante Mariona , Perron Patrice , Wright Robert O. , Hertz-Picciotto Irva , Zhang Hongmei , Karagas Margaret R. , Gehring Ulrike , Marsit Carmen J. , Beilin Lawrence J. , Vonk Judith M. , Jarvelin Marjo-Riitta , Bergström Anna , Örtqvist Anne K. , Ewart Susan , Villa Pia M. , Moore Sophie E. , Willemsen Gonneke , Standaert Arnout R. L. , Håberg Siri E. , Sørensen Thorkild I. A. , Taylor Jack A. , Räikkönen Katri , Yang Ivana V. , Kechris Katerina , Nawrot Tim S. , Silver Matt J. , Gong Yun Yun , Richiardi Lorenzo , Kogevinas Manolis , Litonjua Augusto A. , Eskenazi Brenda , Huen Karen , Mbarek Hamdi , Maguire Rachel L. , Dwyer Terence , Vrijheid Martine , Bouchard Luigi , Baccarelli Andrea A. , Croen Lisa A. , Karmaus Wilfried , Anderson Denise , de Vries Maaike , Sebert Sylvain , Kere Juha , Karlsson Robert , Arshad Syed Hasan , Hämäläinen Esa , Routledge Michael N. , Boomsma Dorret I. , Feinberg Andrew P. , Newschaffer Craig J. , Govarts Eva , Moisse Matthieu , Fallin M. Daniele , Melén Erik , Prentice Andrew M. , Kajantie Eero , Almqvist Catarina , Oken Emily , Dabelea Dana , Boezen H. Marike , Melton Phillip E. , Wright Rosalind J. , Koppelman Gerard H. , Trevisi Letizia , Hivert Marie-France , Sunyer Jordi , Munthe-Kaas Monica C. , Murphy Susan K. , Corpeleijn Eva , Wiemels Joseph , Holland Nina , Herceg Zdenko , Binder Elisabeth B. , Davey Smith George , Jaddoe Vincent W. V. , Lie Rolv T. , Nystad Wenche , London Stephanie J. , Lawlor Debbie A. , Relton Caroline L. , Snieder Harold , Felix Janine F. 
Published: April 2019

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.