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; Chengjian Xu; Leanne K. Kupers; Sam S. Oh; Cathrine Hoyo; Olena Gruzieva; Cilla Soderhal; Lucas A. Salas; Nour Baiz; Hongmei Zhang; Johanna Lepeule; Carlos Ruiz; Symen 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 Jose Saurel-Coubizolles; Bilal M. Quraishi; Jie Ren; Jorg Tost; Juan R. Gonzalez; Marjolein J. Peters; Siri E. Haberg; 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 Bergstrom; Zdenko Herceg; Hector Hernandez-Vargas; Bert Brunekreef; Mariona Pinart; Barbara Heude; Susan Ewart; Jin Yao; Nathanael 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. Anto; Abbas Dehghan; Wilfried Karmaus; Isabella Annesi-Maesano; Jordi Sunyer; Akram Ghantous; Goran Pershagen; Nina Hollands; 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 Melen; Stephanie J. London

doi:10.1016/j.ajhg.2016.02.019

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, Chengjian Xu, Leanne K. Kupers, Sam S. Oh, Cathrine Hoyo, Olena Gruzieva, Cilla Soderhal, Lucas A. Salas, Nour Baiz, 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 Jose Saurel-Coubizolles, Bilal M. Quraishi, Jie Ren, Jorg Tost, Juan R. Gonzalez, Marjolein J. Peters, Siri E. Haberg, 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 Bergstrom, Zdenko Herceg, Hector Hernandez-Vargas, Bert Brunekreef, Mariona Pinart, Barbara Heude, Susan Ewart, Jin Yao, Nathanael 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. Anto, Abbas Dehghan, Wilfried Karmaus, Isabella Annesi-Maesano, Jordi Sunyer, Akram Ghantous, Goran Pershagen, Nina Hollands, 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 Melen, Stephanie J. London^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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 x 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 language	English
Pages (from-to)	680-696
Number of pages	17
Journal	American Journal of Human Genetics
Volume	98
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2016.02.019
Publication status	Published - 7-Apr-2016

Keywords

HYDROCARBON RECEPTOR REPRESSOR
AUTISM SPECTRUM DISORDERS
LYMPH-NODE METASTASIS
LUNG-FUNCTION DECLINE
CIGARETTE-SMOKING
NEUROPILIN-2 EXPRESSION
BREAST-CANCER
IN-UTERO
POSTSYNAPTIC DENSITY
PRENATAL EXPOSURE

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10.1016/j.ajhg.2016.02.019

DNA Methylation in Newborns and Maternal Smoking in Pregnancy GenomeFinal publisher's version, 609 KBLicence: Elsevier

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GECKO Drenthe cohort
Corpeleijn, E. (Creator), Snieder, H. (Creator), Bocca, G. (Creator), Gracchi, V. (Creator) & Hoek, A. (Creator), University of Groningen, 2006
DOI: 10.34760/5f5b80eb0830f, http://www.geckodrenthe.umcg.nl and 2 more links, http://www.birthcohorts.net/birthcohorts/birthcohort/?id=138, https://umcgresearch.org/-/gecko (show fewer)
Dataset

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Joubert, B. R., Felix, J. F., Yousefi, P., Bakulski, K. M., Just, A. C., Breton, C., Reese, S. E., Markunas, C. A., Richmond, R. C., Xu, C., Kupers, L. K., Oh, S. S., Hoyo, C., Gruzieva, O., Soderhal, C., Salas, L. A., Baiz, N., Zhang, H., Lepeule, J., ... 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

@article{fff52abeaa9b4ff2a9355dafe808c658,

title = "DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis",

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 x 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.",

keywords = "HYDROCARBON RECEPTOR REPRESSOR, AUTISM SPECTRUM DISORDERS, LYMPH-NODE METASTASIS, LUNG-FUNCTION DECLINE, CIGARETTE-SMOKING, NEUROPILIN-2 EXPRESSION, BREAST-CANCER, IN-UTERO, POSTSYNAPTIC DENSITY, PRENATAL EXPOSURE",

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

year = "2016",

month = apr,

day = "7",

doi = "10.1016/j.ajhg.2016.02.019",

language = "English",

volume = "98",

pages = "680--696",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

Joubert, BR, Felix, JF, Yousefi, P, Bakulski, KM, Just, AC, Breton, C, Reese, SE, Markunas, CA, Richmond, RC, Xu, C, Kupers, LK, Oh, SS, Hoyo, C, Gruzieva, O, Soderhal, C, Salas, LA, Baiz, 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, Haberg, SE, Xu, Z, van Meurs, JB, Gaunt, TR, Kerkhof, M , Corpeleijn, E, Feinberg, AP, Eng, C, Baccarelli, AA, Neelon, SEB, Bradman, A, Merid, SK, Bergstrom, 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, M-A, Holloway, J, Auffray, C, Tiemeier, HW, Smith, GD, Postma, D, Hivert, M-F, Eskenazi, B, Vrijheid, M, Arshad, H, Anto, JM, Dehghan, A, Karmaus, W, Annesi-Maesano, I, Sunyer, J, Ghantous, A, Pershagen, G, Hollands, N, Murphy, SK, DeMeo, DL, Burchard, EG, Ladd-Acosta, C, Snieder, H, Nystad, W, Koppelman, GH, Relton, CL, Jaddoe, VWV, Wilcox, A, Melen, 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

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, Chengjian

AU - Kupers, Leanne K.

AU - Oh, Sam S.

AU - Hoyo, Cathrine

AU - Gruzieva, Olena

AU - Soderhal, Cilla

AU - Salas, Lucas A.

AU - Baiz, 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 Jose

AU - Quraishi, Bilal M.

AU - Ren, Jie

AU - Tost, Jorg

AU - Gonzalez, Juan R.

AU - Peters, Marjolein J.

AU - Haberg, 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 - Neelon, Sara E. Benjamin

AU - Bradman, Asa

AU - Merid, Simon Kebede

AU - Bergstrom, 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, Nathanael

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 - Anto, Josep M.

AU - Dehghan, Abbas

AU - Karmaus, Wilfried

AU - Annesi-Maesano, Isabella

AU - Sunyer, Jordi

AU - Ghantous, Akram

AU - Pershagen, Goran

AU - Hollands, 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 - Melen, 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 x 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 x 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.

KW - HYDROCARBON RECEPTOR REPRESSOR

KW - AUTISM SPECTRUM DISORDERS

KW - LYMPH-NODE METASTASIS

KW - LUNG-FUNCTION DECLINE

KW - CIGARETTE-SMOKING

KW - NEUROPILIN-2 EXPRESSION

KW - BREAST-CANCER

KW - IN-UTERO

KW - POSTSYNAPTIC DENSITY

KW - PRENATAL EXPOSURE

U2 - 10.1016/j.ajhg.2016.02.019

DO - 10.1016/j.ajhg.2016.02.019

M3 - Article

C2 - 27040690

SN - 0002-9297

VL - 98

SP - 680

EP - 696

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

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

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GECKO Drenthe cohort

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