Title

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: Findings from the pregnancy and childhood epigenetics (PACE) consortium

Authors

Gemma C. Sharp, University of Bristol
Lucas A. Salas, Instituto de Salud Global de Barcelona
Claire Monnereau, Erasmus MC
Catherine Allard, Université de Sherbrooke
Paul Yousefi, Center for Environmental Research and Children's Health
Todd M. Everson, Rollins School of Public Health
Jon Bohlin, Norwegian Institute of Public Health
Zongli Xu, National Institute of Environmental Health Sciences (NIEHS)
Rae Chi Huang, Telethon Kids Institute
Sarah E. Reese, National Institute of Environmental Health Sciences (NIEHS)
Cheng Jian Xu, Universitair Medisch Centrum Groningen
Nour Baïz, Sorbonne Universite
Cathrine Hoyo, NC State University
Golareh Agha, Mailman School of Public Health
Ritu Roy, University of California, San Francisco
John W. Holloway, University of Southampton, Faculty of Medicine
Akram Ghantous, International Agency for Research on Cancer
Simon K. Merid, Karolinska Institutet
Kelly M. Bakulski, University of Michigan School of Public Health
Leanne K. Küpers, University of Bristol
Hongmei Zhang, University of Memphis
Rebecca C. Richmond, University of Bristol
Christian M. Page, Norwegian Institute of Public Health
Liesbeth Duijts, Erasmus MC
Rolv T. Lie, Universitetet i Bergen
Phillip E. Melton, Curtin University
Judith M. Vonk, Universitair Medisch Centrum Groningen
Ellen A. Nohr, Syddansk Universitet
Clar Lynda Williams-DeVane, North Carolina Central University
Karen Huen, Center for Environmental Research and Children's Health
Sheryl L. Rifas-Shiman, Harvard Medical School
Carlos Ruiz-Arenas, Instituto de Salud Global de Barcelona
Semira Gonseth, University of California, San Francisco

Abstract

Pre-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 the 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 (1 kg/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 the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a6causal 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.

Publication Title

Human Molecular Genetics

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