DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

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

Research output: Contribution to journalArticle (Academic Journal)

321 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)680-696
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number4
Early online date31 Mar 2016
Publication statusPublished - 7 Apr 2016

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    MRC UoB UNITE Unit - Programme 1

    Davey Smith, G.


    Project: Research

    MRC UoB UNITE Unit - Programme 2

    Relton, C. L. & Relton, C. L.


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    Flach, P. A., Gaunt, T. R. & Gaunt, T. R.


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  • Cite this

    Joubert, BR., Felix, JF., Yousefi, P., Bakulski, KM., Just, AC., Breton, C., Reese, S. E., Markunas, CA., Richmond, R. C., Xu, C-J., Kupers, L. K., Oh, SS., Hoyo, C., Gruzieva, O., Söderhäll, C., Salas, LA., Baïz, N., Zhang, H., Lepeule, J., ... London, SJ. (2016). DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. American Journal of Human Genetics, 98(4), 680-696. https://doi.org/10.1016/j.ajhg.2016.02.019