A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation

Giulietta S. Monasso; Thanh T. Hoang; Giulia Mancano; Sílvia Fernández-Barrés; John Dou; Vincent W.V. Jaddoe; Christian M. Page; Laura Johnson; Mariona Bustamante; Kelly M. Bakulski; Siri E. Håberg; Per M. Ueland; Thomas Battram; Simon K. Merid; Erik Melén; Doretta Caramaschi; Leanne K. Küpers; Jordi Sunyer; Wenche Nystad; Sandra G. Heil; Rebecca J. Schmidt; Martine Vrijheid; Gemma C. Sharp; Stephanie J. London; Janine F. Felix

doi:10.1080/15592294.2023.2202835

A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation

Giulietta S. Monasso, Thanh T. Hoang, Giulia Mancano, Sílvia Fernández-Barrés, John Dou, Vincent W.V. Jaddoe, Christian M. Page, Laura Johnson, Mariona Bustamante, Kelly M. Bakulski, Siri E. Håberg, Per M. Ueland, Thomas Battram, Simon K. Merid, Erik Melén, Doretta Caramaschi, Leanne K. Küpers, Jordi Sunyer, Wenche Nystad, Sandra G. HeilRebecca J. Schmidt, Martine Vrijheid, Gemma C. Sharp, Stephanie J. London, Janine F. Felix^*

^*Corresponding author for this work

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Abstract

Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4–10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (P _FDR<0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.

Original language	English
Article number	2202835
Journal	Epigenetics
Volume	18
Issue number	1
Early online date	24 Apr 2023
DOIs	https://doi.org/10.1080/15592294.2023.2202835
Publication status	Published - 2023

Bibliographical note

Funding Information:
The work was supported by the Medical Research Council [MR/S009310/1]; European Research Council [ERC-2014-CoG-648916]. For all studies, acknowledgements can be found in Supplementary Information: Acknowledgements. For all studies, funding statements can be found in Supplementary Information: Funding.

Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

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A meta-analysis of epigenome-wide association studies on pregnancy vitamiFinal published version, 3.13 MBLicence: CC BY

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Monasso, G. S., Hoang, T. T., Mancano, G., Fernández-Barrés, S., Dou, J., Jaddoe, V. W. V., Page, C. M., Johnson, L., Bustamante, M., Bakulski, K. M., Håberg, S. E., Ueland, P. M., Battram, T., Merid, S. K., Melén, E., Caramaschi, D., Küpers, L. K., Sunyer, J., Nystad, W., ... Felix, J. F. (2023). A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation. Epigenetics, 18(1), Article 2202835. https://doi.org/10.1080/15592294.2023.2202835

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abstract = "Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4–10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (P FDR<0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.",

author = "Monasso, {Giulietta S.} and Hoang, {Thanh T.} and Giulia Mancano and S{\'i}lvia Fern{\'a}ndez-Barr{\'e}s and John Dou and Jaddoe, {Vincent W.V.} and Page, {Christian M.} and Laura Johnson and Mariona Bustamante and Bakulski, {Kelly M.} and H{\aa}berg, {Siri E.} and Ueland, {Per M.} and Thomas Battram and Merid, {Simon K.} and Erik Mel{\'e}n and Doretta Caramaschi and K{\"u}pers, {Leanne K.} and Jordi Sunyer and Wenche Nystad and Heil, {Sandra G.} and Schmidt, {Rebecca J.} and Martine Vrijheid and Sharp, {Gemma C.} and London, {Stephanie J.} and Felix, {Janine F.}",

note = "Funding Information: The work was supported by the Medical Research Council [MR/S009310/1]; European Research Council [ERC-2014-CoG-648916]. For all studies, acknowledgements can be found in Supplementary Information: Acknowledgements. For all studies, funding statements can be found in Supplementary Information: Funding. Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.",

year = "2023",

doi = "10.1080/15592294.2023.2202835",

language = "English",

volume = "18",

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Monasso, GS, Hoang, TT, Mancano, G, Fernández-Barrés, S, Dou, J, Jaddoe, VWV, Page, CM, Johnson, L, Bustamante, M, Bakulski, KM, Håberg, SE, Ueland, PM, Battram, T, Merid, SK, Melén, E, Caramaschi, D, Küpers, LK, Sunyer, J, Nystad, W, Heil, SG, Schmidt, RJ, Vrijheid, M, Sharp, GC, London, SJ & Felix, JF 2023, 'A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation', Epigenetics, vol. 18, no. 1, 2202835. https://doi.org/10.1080/15592294.2023.2202835

TY - JOUR

T1 - A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation

AU - Monasso, Giulietta S.

AU - Hoang, Thanh T.

AU - Mancano, Giulia

AU - Fernández-Barrés, Sílvia

AU - Dou, John

AU - Jaddoe, Vincent W.V.

AU - Page, Christian M.

AU - Johnson, Laura

AU - Bustamante, Mariona

AU - Bakulski, Kelly M.

AU - Håberg, Siri E.

AU - Ueland, Per M.

AU - Battram, Thomas

AU - Merid, Simon K.

AU - Melén, Erik

AU - Caramaschi, Doretta

AU - Küpers, Leanne K.

AU - Sunyer, Jordi

AU - Nystad, Wenche

AU - Heil, Sandra G.

AU - Schmidt, Rebecca J.

AU - Vrijheid, Martine

AU - Sharp, Gemma C.

AU - London, Stephanie J.

AU - Felix, Janine F.

N1 - Funding Information: The work was supported by the Medical Research Council [MR/S009310/1]; European Research Council [ERC-2014-CoG-648916]. For all studies, acknowledgements can be found in Supplementary Information: Acknowledgements. For all studies, funding statements can be found in Supplementary Information: Funding. Publisher Copyright: © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

PY - 2023

Y1 - 2023

N2 - Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4–10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (P FDR<0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.

AB - Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4–10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (P FDR<0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.

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A meta-analysis of epigenome-wide association studies on pregnancy vitamin B12 concentrations and offspring DNA methylation

Abstract

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