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. Küpers, 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 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

270 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)680-696
Number of pages17
JournalAmerican Journal of Human Genetics
Volume98
Issue number4
DOIs
StatePublished - Apr 7 2016
Externally publishedYes

Fingerprint

DNA Methylation
Meta-Analysis
Smoking
Mothers
Newborn Infant
Genome
Pregnancy
Epigenomics
Methylation
Social Adjustment
Critical Pathways
Genes
Asthma
Public Health
Gene Expression
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Joubert, B. R., Felix, J. F., Yousefi, P., Bakulski, K. M., Just, A. C., Breton, C., ... London, S. J. (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

DNA Methylation in Newborns and Maternal Smoking in Pregnancy : Genome-wide Consortium Meta-analysis. / 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; London, Stephanie J.

In: American Journal of Human Genetics, Vol. 98, No. 4, 07.04.2016, p. 680-696.

Research output: Contribution to journalArticle

Joubert, BR, Felix, JF, Yousefi, P, Bakulski, KM, Just, AC, Breton, C, Reese, SE, Markunas, CA, Richmond, RC, Xu, CJ, Küpers, LK, Oh, SS, Hoyo, C, Gruzieva, O, Söderhäll, C, Salas, LA, Baïz, N, Zhang, H, Lepeule, J, Ruiz, C, Ligthart, S, Wang, T, Taylor, JA, Duijts, L, Sharp, GC, Jankipersadsing, SA, Nilsen, RM, Vaez, A, Fallin, MD, Hu, D, Litonjua, AA, Fuemmeler, BF, Huen, K, Kere, J, Kull, I, Munthe-Kaas, MC, Gehring, U, Bustamante, M, Saurel-Coubizolles, MJ, Quraishi, BM, Ren, J, Tost, J, Gonzalez, JR, Peters, MJ, Håberg, SE, Xu, Z, Van Meurs, JB, Gaunt, TR, Kerkhof, M, Corpeleijn, E, Feinberg, AP, Eng, C, Baccarelli, AA, Benjamin Neelon, SE, Bradman, A, Merid, SK, Bergström, A, Herceg, Z, Hernandez-Vargas, H, Brunekreef, B, Pinart, M, Heude, B, Ewart, S, Yao, J, Lemonnier, N, Franco, OH, Wu, MC, Hofman, A, McArdle, W, Van Der Vlies, P, Falahi, F, Gillman, MW, Barcellos, LF, Kumar, A, Wickman, M, Guerra, S, Charles, MA, Holloway, J, Auffray, C, Tiemeier, HW, Smith, GD, Postma, D, Hivert, MF, Eskenazi, B, Vrijheid, M, Arshad, H, Antó, JM, Dehghan, A, Karmaus, W, Annesi-Maesano, I, Sunyer, J, Ghantous, A, Pershagen, G, Holland, N, Murphy, SK, Demeo, DL, Burchard, EG, Ladd-Acosta, C, Snieder, H, Nystad, W, Koppelman, GH, Relton, CL, Jaddoe, VWV, Wilcox, A, Melén, E & London, SJ 2016, 'DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis', American Journal of Human Genetics, vol. 98, no. 4, pp. 680-696. https://doi.org/10.1016/j.ajhg.2016.02.019
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 ; London, Stephanie J. / DNA Methylation in Newborns and Maternal Smoking in Pregnancy : Genome-wide Consortium Meta-analysis. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 4. pp. 680-696.
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TY - JOUR

T1 - DNA Methylation in Newborns and Maternal Smoking in Pregnancy

T2 - Genome-wide Consortium Meta-analysis

AU - Joubert, Bonnie R.

AU - Felix, Janine F.

AU - Yousefi, Paul

AU - Bakulski, Kelly M.

AU - Just, Allan C.

AU - Breton, Carrie

AU - Reese, Sarah E.

AU - Markunas, Christina A.

AU - Richmond, Rebecca C.

AU - Xu, Cheng Jian

AU - Küpers, Leanne K.

AU - Oh, Sam S.

AU - Hoyo, Cathrine

AU - Gruzieva, Olena

AU - Söderhäll, Cilla

AU - Salas, Lucas A.

AU - Baïz, Nour

AU - Zhang, Hongmei

AU - Lepeule, Johanna

AU - Ruiz, Carlos

AU - Ligthart, Symen

AU - Wang, Tianyuan

AU - Taylor, Jack A.

AU - Duijts, Liesbeth

AU - Sharp, Gemma C.

AU - Jankipersadsing, Soesma A.

AU - Nilsen, Roy M.

AU - Vaez, Ahmad

AU - Fallin, M. Daniele

AU - Hu, Donglei

AU - Litonjua, Augusto A.

AU - Fuemmeler, Bernard F.

AU - Huen, Karen

AU - Kere, Juha

AU - Kull, Inger

AU - Munthe-Kaas, Monica Cheng

AU - Gehring, Ulrike

AU - Bustamante, Mariona

AU - Saurel-Coubizolles, Marie José

AU - Quraishi, Bilal M.

AU - Ren, Jie

AU - Tost, Jörg

AU - Gonzalez, Juan R.

AU - Peters, Marjolein J.

AU - Håberg, Siri E.

AU - Xu, Zongli

AU - Van Meurs, Joyce B.

AU - Gaunt, Tom R.

AU - Kerkhof, Marjan

AU - Corpeleijn, Eva

AU - Feinberg, Andrew P.

AU - Eng, Celeste

AU - Baccarelli, Andrea A.

AU - Benjamin Neelon, Sara E.

AU - Bradman, Asa

AU - Merid, Simon Kebede

AU - Bergström, Anna

AU - Herceg, Zdenko

AU - Hernandez-Vargas, Hector

AU - Brunekreef, Bert

AU - Pinart, Mariona

AU - Heude, Barbara

AU - Ewart, Susan

AU - Yao, Jin

AU - Lemonnier, Nathanaël

AU - Franco, Oscar H.

AU - Wu, Michael C.

AU - Hofman, Albert

AU - McArdle, Wendy

AU - Van Der Vlies, Pieter

AU - Falahi, Fahimeh

AU - Gillman, Matthew W.

AU - Barcellos, Lisa F.

AU - Kumar, Ashish

AU - Wickman, Magnus

AU - Guerra, Stefano

AU - Charles, Marie Aline

AU - Holloway, John

AU - Auffray, Charles

AU - Tiemeier, Henning W.

AU - Smith, George Davey

AU - Postma, Dirkje

AU - Hivert, Marie France

AU - Eskenazi, Brenda

AU - Vrijheid, Martine

AU - Arshad, Hasan

AU - Antó, Josep M.

AU - Dehghan, Abbas

AU - Karmaus, Wilfried

AU - Annesi-Maesano, Isabella

AU - Sunyer, Jordi

AU - Ghantous, Akram

AU - Pershagen, Göran

AU - Holland, Nina

AU - Murphy, Susan K.

AU - Demeo, Dawn L.

AU - Burchard, Esteban G.

AU - Ladd-Acosta, Christine

AU - Snieder, Harold

AU - Nystad, Wenche

AU - Koppelman, Gerard H.

AU - Relton, Caroline L.

AU - Jaddoe, Vincent W.V.

AU - Wilcox, Allen

AU - Melén, Erik

AU - London, Stephanie J.

PY - 2016/4/7

Y1 - 2016/4/7

N2 - 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.

AB - 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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DO - 10.1016/j.ajhg.2016.02.019

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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