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 | |
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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- DNA Methylation in Newborns and Maternal Smoking in Pregnancy GenomeFinal publisher's version, 609 KBLicence: Elsevier
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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, Chengjian; Kupers, Leanne K.; Oh, Sam S.; Hoyo, Cathrine; Gruzieva, Olena; Soderhal, Cilla; Salas, Lucas A.; Baiz, 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 Jose; Quraishi, Bilal M.; Ren, Jie; Tost, Jorg; Gonzalez, Juan R.; Peters, Marjolein J.; Haberg, Siri E.; Xu, Zongli; van Meurs, Joyce B.; Gaunt, Tom R.; Kerkhof, Marjan; Corpeleijn, Eva; Feinberg, Andrew P.; Eng, Celeste; Baccarelli, Andrea A.; Neelon, Sara E. Benjamin; Bradman, Asa; Merid, Simon Kebede; Bergstrom, Anna; Herceg, Zdenko; Hernandez-Vargas, Hector; Brunekreef, Bert; Pinart, Mariona; Heude, Barbara; Ewart, Susan; Yao, Jin; Lemonnier, Nathanael; 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; Anto, Josep M.; Dehghan, Abbas; Karmaus, Wilfried; Annesi-Maesano, Isabella; Sunyer, Jordi; Ghantous, Akram; Pershagen, Goran; Hollands, 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; Melen, Erik; London, Stephanie J.
In: American Journal of Human Genetics, Vol. 98, No. 4, 07.04.2016, p. 680-696.Research output: Contribution to journal › Article › Academic › peer-review
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.
N1 - Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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
VL - 98
SP - 680
EP - 696
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -