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

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium
Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium
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 acausal 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
0964-6906
4067-4085
Sharp, Gemma C.
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Salas, Lucas A.
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Monnereau, Claire
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Allard, Catherine
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Yousefi, Paul
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Relton, Caroline L.
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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 K., 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, Clarlynda, 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 M., Suderman, Matthew, Magnus, Maria C., Jaddoe, Vincent W.V., 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., Davey Smith, George, 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 I.A., Koppelman, Gerard H., Newnham, John P., Wilcox, Allen J., Nystad, Wenche, London, Stephanie J., Felix, Janine F. and Relton, Caroline L. (2017) Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium. Human Molecular Genetics, 26 (20), 4067-4085. (doi:10.1093/hmg/ddx290).

Record type: Article

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 acausal 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

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Accepted/In Press date: 17 July 2017
e-pub ahead of print date: 21 July 2017
Published date: 15 October 2017

Identifiers

Local EPrints ID: 413451
URI: https://eprints.soton.ac.uk/id/eprint/413451
ISSN: 0964-6906
PURE UUID: 319bd67a-81cb-408d-b12b-a6b2fb84d460
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for Faisal I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X

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Date deposited: 24 Aug 2017 16:30
Last modified: 10 Dec 2019 01:52

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Contributors

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

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