Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: Findings from the Pregnancy and Childhood Epigenetics (PACE) consortium
Authors: Sharp Gemma C , Salas Lucas A , Monnereau Claire , Allard Catherine , Yousefi Paul , Everson Todd M , Bohlin Jon , Xu Zongli , Huang Rae-Chi , Reese Sarah E , Xu Cheng-Jian , Baïz Nour , Hoyo Cathrine , Agha Golareh , Roy Ritu , Holloway John W , Ghantous Akram , Merid Simon Kebede , Bakulski Kelly M , Küpers Leanne K , Zhang Hongmei , Richmond Rebecca C , Page Christian M , Duijts Liesbeth , Lie Rolv T , Melton Phillip E , Vonk Judith M , Nohr Ellen A , Williams-DeVane CharLynda , Huen Karen , Rifas-Shiman Sheryl L , Ruiz-Arenas Carlos , Gonseth Semira , Rezwan Faisal I , Herceg Zdenko , Ekström Sandra , Croen Lisa , Falahi Fahimeh , Perron Patrice , Karagas Margaret R , Quraishi Bilal Mohammed , Suderman Matthew , Magnus Maria C , Jaddoe Vincent WV , Taylor Jack A , Anderson Denise , Zhao Shanshan , Smit Henriette A , Josey Michele J , Bradman Asa , Baccarelli Andrea A , Bustamante Mariona , Håberg Siri E , Pershagen Göran , Hertz-Picciotto Irva , Newschaffer Craig , Corpeleijn Eva , Bouchard Luigi , Lawlor Debbie A , Maguire Rachel L , Barcellos Lisa F , Smith George Davey , Eskenazi Brenda , Karmaus Wilfried , Marsit Carmen J , Hivert Marie-France , Snieder Harold , Fallin M Daniele , Melén Erik , Munthe-Kaas Monica C , Arshad Hasan , Wiemels Joseph L , Annesi-Maesano Isabella , Vrijheid Martine , Oken Emily , Holland Nina , Murphy Susan K , Sørensen Thorkild IA , Koppelman Gerard H , Newnham John P , Wilcox Allen J , Nystad Wenche , London Stephanie J , Felix Janine F , Relton Caroline L 
Published: April 2017

AbstractPre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute.Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents.In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1kg/m2), P<1.06*10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites.In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.