The University of Southampton
University of Southampton Institutional Repository

DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis

DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis
DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis
Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10-16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
0002-9297
680-696
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London, Stephanie J.
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Joubert, Bonnie R., Felix, Janine F., Yousefi, Paul, Bakulski, Kelly M., Just, Allan C., Breton, Carrie, Reese, Sarah E., Markunas, Christina A., Richmond, Rebecca C., Xu, Cheng-Jian, Küpers, Leanne K., Oh, Sam S., Hoyo, Cathrine, Gruzieva, Olena, Söderhäll, Cilla, Salas, Lucas A., Baïz, Nour, Zhang, Hongmei, Lepeule, Johanna, Ruiz, Carlos, Ligthart, Symen, Wang, Tianyuan, Taylor, Jack A., Duijts, Liesbeth, Sharp, Gemma C., Jankipersadsing, Soesma A., Nilsen, Roy M., Vaez, Ahmad, Fallin, M. Daniele, Hu, Donglei, Litonjua, Augusto A., Fuemmeler, Bernard F., Huen, Karen, Kere, Juha, Kull, Inger, Munthe-Kaas, Monica Cheng, Gehring, Ulrike, Bustamante, Mariona, Saurel-Coubizolles, Marie José, Quraishi, Bilal M., Ren, Jie, Tost, Jörg, Gonzalez, Juan R., Peters, Marjolein J., Håberg, Siri E., Xu, Zongli, van Meurs, Joyce B., Gaunt, Tom R., Kerkhof, Marjan, Corpeleijn, Eva, Feinberg, Andrew P., Eng, Celeste, Baccarelli, Andrea A., Benjamin Neelon, Sara E., Bradman, Asa, Merid, Simon Kebede, Bergström, Anna, Herceg, Zdenko, Hernandez-Vargas, Hector, Brunekreef, Bert, Pinart, Mariona, Heude, Barbara, Ewart, Susan, Yao, Jin, Lemonnier, Nathanaël, Franco, Oscar H., Wu, Michael C., Hofman, Albert, McArdle, Wendy, Van der Vlies, Pieter, Falahi, Fahimeh, Gillman, Matthew W., Barcellos, Lisa F., Kumar, Ashish, Wickman, Magnus, Guerra, Stefano, Charles, Marie-Aline, Holloway, John, Auffray, Charles, Tiemeier, Henning W., Smith, George Davey, Postma, Dirkje, Hivert, Marie-France, Eskenazi, Brenda, Vrijheid, Martine, Arshad, Hasan, Antó, Josep M., Dehghan, Abbas, Karmaus, Wilfried, Annesi-Maesano, Isabella, Sunyer, Jordi, Ghantous, Akram, Pershagen, Göran, Holland, Nina, Murphy, Susan K., DeMeo, Dawn L., Burchard, Esteban G., Ladd-Acosta, Christine, Snieder, Harold, Nystad, Wenche, Koppelman, Gerard H., Relton, Caroline L., Jaddoe, Vincent W.V., Wilcox, Allen, Melén, Erik and London, Stephanie J. (2016) DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. The American Journal of Human Genetics, 98 (4), 680-696. (doi:10.1016/j.ajhg.2016.02.019).

Record type: Article

Abstract

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10-16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

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PACE_Smoking.Manuscript.AJHG.Revised.forCoauthorReview.pdf - Accepted Manuscript
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Accepted/In Press date: 20 February 2016
e-pub ahead of print date: 31 March 2016
Published date: 7 April 2016
Organisations: NIHR Southampton Biomedical Research Centre, Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 390708
URI: https://eprints.soton.ac.uk/id/eprint/390708
ISSN: 0002-9297
PURE UUID: b882c49e-8ba0-4072-973c-7af0ab970a77
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 04 Apr 2016 15:36
Last modified: 03 Dec 2019 01:58

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Contributors

Author: Bonnie R. Joubert
Author: Janine F. Felix
Author: Paul Yousefi
Author: Kelly M. Bakulski
Author: Allan C. Just
Author: Carrie Breton
Author: Sarah E. Reese
Author: Christina A. Markunas
Author: Rebecca C. Richmond
Author: Cheng-Jian Xu
Author: Leanne K. Küpers
Author: Sam S. Oh
Author: Cathrine Hoyo
Author: Olena Gruzieva
Author: Cilla Söderhäll
Author: Lucas A. Salas
Author: Nour Baïz
Author: Hongmei Zhang
Author: Johanna Lepeule
Author: Carlos Ruiz
Author: Symen Ligthart
Author: Tianyuan Wang
Author: Jack A. Taylor
Author: Liesbeth Duijts
Author: Gemma C. Sharp
Author: Soesma A. Jankipersadsing
Author: Roy M. Nilsen
Author: Ahmad Vaez
Author: M. Daniele Fallin
Author: Donglei Hu
Author: Augusto A. Litonjua
Author: Bernard F. Fuemmeler
Author: Karen Huen
Author: Juha Kere
Author: Inger Kull
Author: Monica Cheng Munthe-Kaas
Author: Ulrike Gehring
Author: Mariona Bustamante
Author: Marie José Saurel-Coubizolles
Author: Bilal M. Quraishi
Author: Jie Ren
Author: Jörg Tost
Author: Juan R. Gonzalez
Author: Marjolein J. Peters
Author: Siri E. Håberg
Author: Zongli Xu
Author: Joyce B. van Meurs
Author: Tom R. Gaunt
Author: Marjan Kerkhof
Author: Eva Corpeleijn
Author: Andrew P. Feinberg
Author: Celeste Eng
Author: Andrea A. Baccarelli
Author: Sara E. Benjamin Neelon
Author: Asa Bradman
Author: Simon Kebede Merid
Author: Anna Bergström
Author: Zdenko Herceg
Author: Hector Hernandez-Vargas
Author: Bert Brunekreef
Author: Mariona Pinart
Author: Barbara Heude
Author: Susan Ewart
Author: Jin Yao
Author: Nathanaël Lemonnier
Author: Oscar H. Franco
Author: Michael C. Wu
Author: Albert Hofman
Author: Wendy McArdle
Author: Pieter Van der Vlies
Author: Fahimeh Falahi
Author: Matthew W. Gillman
Author: Lisa F. Barcellos
Author: Ashish Kumar
Author: Magnus Wickman
Author: Stefano Guerra
Author: Marie-Aline Charles
Author: John Holloway ORCID iD
Author: Charles Auffray
Author: Henning W. Tiemeier
Author: George Davey Smith
Author: Dirkje Postma
Author: Marie-France Hivert
Author: Brenda Eskenazi
Author: Martine Vrijheid
Author: Hasan Arshad
Author: Josep M. Antó
Author: Abbas Dehghan
Author: Wilfried Karmaus
Author: Isabella Annesi-Maesano
Author: Jordi Sunyer
Author: Akram Ghantous
Author: Göran Pershagen
Author: Nina Holland
Author: Susan K. Murphy
Author: Dawn L. DeMeo
Author: Esteban G. Burchard
Author: Christine Ladd-Acosta
Author: Harold Snieder
Author: Wenche Nystad
Author: Gerard H. Koppelman
Author: Caroline L. Relton
Author: Vincent W.V. Jaddoe
Author: Allen Wilcox
Author: Erik Melén
Author: Stephanie J. London

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