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

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

doi:10.1093/hmg/ddx290

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

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

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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.

Original language	English
Journal	Human Molecular Genetics
Volume	26
Issue number	20
Pages (from-to)	4067-4085
Number of pages	19
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddx290
Publication status	Published - 15 Oct 2017

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/hmg/ddx290

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortiumFinal published version, 1.09 MBLicence: CC BY

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Sharp, G. C., Salas, L. A., Monnereau, C., Allard, C., Yousefi, P., Everson, T. M., Bohlin, J., Xu, Z., Huang, R-C., Reese, S. E., Xu, C-J., Baïz, N., Hoyo, C., Agha, G., Roy, R., Holloway, J. W., Ghantous, A., Merid, S. K., Bakulski, K. M., ... Relton, C. 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. https://doi.org/10.1093/hmg/ddx290

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation : findings from the pregnancy and childhood epigenetics (PACE) consortium. / Sharp, Gemma C; Salas, Lucas A; Monnereau, Claire et al.

In: Human Molecular Genetics, Vol. 26, No. 20, 15.10.2017, p. 4067-4085.

Research output: Contribution to journal › Journal article › Research › peer-review

Sharp, GC, Salas, LA, Monnereau, C, Allard, C, Yousefi, P, Everson, TM, Bohlin, J, Xu, Z, Huang, R-C, Reese, SE, Xu, C-J, Baïz, N, Hoyo, C, Agha, G, Roy, R, Holloway, JW, Ghantous, A, Merid, SK, Bakulski, KM, Küpers, LK, Zhang, H, Richmond, RC, Page, CM, Duijts, L, Lie, RT, Melton, PE, Vonk, JM, Nohr, EA, Williams-DeVane, C, Huen, K, Rifas-Shiman, SL, Ruiz-Arenas, C, Gonseth, S, Rezwan, FI, Herceg, Z, Ekström, S, Croen, L, Falahi, F, Perron, P, Karagas, MR, Quraishi, BM, Suderman, M, Magnus, MC, Jaddoe, VWV, Taylor, JA, Anderson, D, Zhao, S, Smit, HA, Josey, MJ, Bradman, A, Baccarelli, AA, Bustamante, M, Håberg, SE, Pershagen, G, Hertz-Picciotto, I, Newschaffer, C, Corpeleijn, E, Bouchard, L, Lawlor, DA, Maguire, RL, Barcellos, LF, Davey Smith, G, Eskenazi, B, Karmaus, W, Marsit, CJ, Hivert, M-F, Snieder, H, Fallin, MD, Melén, E, Munthe-Kaas, MC, Arshad, H, Wiemels, JL, Annesi-Maesano, I, Vrijheid, M, Oken, E, Holland, N, Murphy, SK, Sørensen, TIA, Koppelman, GH, Newnham, JP, Wilcox, AJ, Nystad, W, London, SJ, Felix, JF & Relton, CL 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, vol. 26, no. 20, pp. 4067-4085. https://doi.org/10.1093/hmg/ddx290

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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.",

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AU - Sharp, Gemma C

AU - Salas, Lucas A

AU - Monnereau, Claire

AU - Allard, Catherine

AU - Yousefi, Paul

AU - Everson, Todd M

AU - Bohlin, Jon

AU - Xu, Zongli

AU - Huang, Rae-Chi

AU - Reese, Sarah E

AU - Xu, Cheng-Jian

AU - Baïz, Nour

AU - Hoyo, Cathrine

AU - Agha, Golareh

AU - Roy, Ritu

AU - Holloway, John W

AU - Ghantous, Akram

AU - Merid, Simon K

AU - Bakulski, Kelly M

AU - Küpers, Leanne K

AU - Zhang, Hongmei

AU - Richmond, Rebecca C

AU - Page, Christian M

AU - Duijts, Liesbeth

AU - Lie, Rolv T

AU - Melton, Phillip E

AU - Vonk, Judith M

AU - Nohr, Ellen A

AU - Williams-DeVane, ClarLynda

AU - Huen, Karen

AU - Rifas-Shiman, Sheryl L

AU - Ruiz-Arenas, Carlos

AU - Gonseth, Semira

AU - Rezwan, Faisal I

AU - Herceg, Zdenko

AU - Ekström, Sandra

AU - Croen, Lisa

AU - Falahi, Fahimeh

AU - Perron, Patrice

AU - Karagas, Margaret R

AU - Quraishi, Bilal M

AU - Suderman, Matthew

AU - Magnus, Maria C

AU - Jaddoe, Vincent W V

AU - Taylor, Jack A

AU - Anderson, Denise

AU - Zhao, Shanshan

AU - Smit, Henriette A

AU - Josey, Michele J

AU - Bradman, Asa

AU - Baccarelli, Andrea A

AU - Bustamante, Mariona

AU - Håberg, Siri E

AU - Pershagen, Göran

AU - Hertz-Picciotto, Irva

AU - Newschaffer, Craig

AU - Corpeleijn, Eva

AU - Bouchard, Luigi

AU - Lawlor, Debbie A

AU - Maguire, Rachel L

AU - Barcellos, Lisa F

AU - Davey Smith, George

AU - Eskenazi, Brenda

AU - Karmaus, Wilfried

AU - Marsit, Carmen J

AU - Hivert, Marie-France

AU - Snieder, Harold

AU - Fallin, M Daniele

AU - Melén, Erik

AU - Munthe-Kaas, Monica C

AU - Arshad, Hasan

AU - Wiemels, Joseph L

AU - Annesi-Maesano, Isabella

AU - Vrijheid, Martine

AU - Oken, Emily

AU - Holland, Nina

AU - Murphy, Susan K

AU - Sørensen, Thorkild I A

AU - Koppelman, Gerard H

AU - Newnham, John P

AU - Wilcox, Allen J

AU - Nystad, Wenche

AU - London, Stephanie J

AU - Felix, Janine F

AU - Relton, Caroline L

PY - 2017/10/15

Y1 - 2017/10/15

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1093/hmg/ddx290

DO - 10.1093/hmg/ddx290

M3 - Journal article

C2 - 29016858

SN - 0964-6906

VL - 26

SP - 4067

EP - 4085

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 20

ER -

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

Abstract

Keywords

UN SDGs

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