Epigenetic Signatures of Cigarette Smoking

Roby Joehanes, Allan C. Just, Riccardo E. Marioni, Luke C. Pilling, Lindsay M. Reynolds, Pooja R. Mandaviya, Weihua Guan, Tao Xu, Cathy E. Elks, Stella Aslibekyan, Hortensia Moreno-Macias, Jennifer A. Smith, Jennifer A. Brody, Radhika Dhingra, Paul Yousefi, James S. Pankow, Sonja Kunze, Sonia H. Shah, Allan F. McRae, Kurt LohmanJin Sha, Devin M. Absher, Luigi Ferrucci, Wei Zhao, Ellen W. Demerath, Jan Bressler, Megan L. Grove, Tianxiao Huan, Chunyu Liu, Michael M. Mendelson, Chen Yao, Douglas P. Kiel, Annette Peters, Rui Wang-Sattler, Peter M. Visscher, Naomi R. Wray, John M. Starr, Jingzhong Ding, Carlos J. Rodriguez, Nicholas J. Wareham, Marguerite R. Irvin, Degui Zhi, Myrto Barrdahl, Paolo Vineis, Srikant Ambatipudi, André G. Uitterlinden, Albert Hofman, Joel Schwartz, Elena Colicino, Lifang Hou, Pantel S. Vokonas, Dena G. Hernandez, Andrew B. Singleton, Stefania Bandinelli, Stephen T Turner, Erin B. Ware, Alicia K. Smith, Torsten Klengel, Elisabeth B. Binder, Bruce M. Psaty, Kent D. Taylor, Sina A. Gharib, Brenton R. Swenson, Liming Liang, Dawn L. Demeo, George T. O'Connor, Zdenko Herceg, Kerry J. Ressler, Karen N. Conneely, Nona Sotoodehnia, Sharon L R Kardia, David Melzer, Andrea A. Baccarelli, Joyce B J Van Meurs, Isabelle Romieu, Donna K. Arnett, Ken K. Ong, Yongmei Liu, Melanie Waldenberger, Ian J. Deary, Myriam Fornage, Daniel Levy, Stephanie J. London

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

Background-DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results-To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10-7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10-7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions-Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

Original languageEnglish (US)
Pages (from-to)436-447
Number of pages12
JournalCirculation: Cardiovascular Genetics
Volume9
Issue number5
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Fingerprint

Epigenomics
Smoking
DNA Methylation
Methylation
Tobacco
Genome
Smoking Cessation
Genes
Lung Neoplasms
Cytosine
Guanine
Smoke
Osteoporosis
Meta-Analysis
Heart Diseases
Biomarkers
Phosphates
Gene Expression
DNA
Health

Keywords

  • biomarkers
  • genome-wide association study
  • meta-analysis
  • methylation
  • smoking

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Joehanes, R., Just, A. C., Marioni, R. E., Pilling, L. C., Reynolds, L. M., Mandaviya, P. R., ... London, S. J. (2016). Epigenetic Signatures of Cigarette Smoking. Circulation: Cardiovascular Genetics, 9(5), 436-447. https://doi.org/10.1161/CIRCGENETICS.116.001506

Epigenetic Signatures of Cigarette Smoking. / Joehanes, Roby; Just, Allan C.; Marioni, Riccardo E.; Pilling, Luke C.; Reynolds, Lindsay M.; Mandaviya, Pooja R.; Guan, Weihua; Xu, Tao; Elks, Cathy E.; Aslibekyan, Stella; Moreno-Macias, Hortensia; Smith, Jennifer A.; Brody, Jennifer A.; Dhingra, Radhika; Yousefi, Paul; Pankow, James S.; Kunze, Sonja; Shah, Sonia H.; McRae, Allan F.; Lohman, Kurt; Sha, Jin; Absher, Devin M.; Ferrucci, Luigi; Zhao, Wei; Demerath, Ellen W.; Bressler, Jan; Grove, Megan L.; Huan, Tianxiao; Liu, Chunyu; Mendelson, Michael M.; Yao, Chen; Kiel, Douglas P.; Peters, Annette; Wang-Sattler, Rui; Visscher, Peter M.; Wray, Naomi R.; Starr, John M.; Ding, Jingzhong; Rodriguez, Carlos J.; Wareham, Nicholas J.; Irvin, Marguerite R.; Zhi, Degui; Barrdahl, Myrto; Vineis, Paolo; Ambatipudi, Srikant; Uitterlinden, André G.; Hofman, Albert; Schwartz, Joel; Colicino, Elena; Hou, Lifang; Vokonas, Pantel S.; Hernandez, Dena G.; Singleton, Andrew B.; Bandinelli, Stefania; Turner, Stephen T; Ware, Erin B.; Smith, Alicia K.; Klengel, Torsten; Binder, Elisabeth B.; Psaty, Bruce M.; Taylor, Kent D.; Gharib, Sina A.; Swenson, Brenton R.; Liang, Liming; Demeo, Dawn L.; O'Connor, George T.; Herceg, Zdenko; Ressler, Kerry J.; Conneely, Karen N.; Sotoodehnia, Nona; Kardia, Sharon L R; Melzer, David; Baccarelli, Andrea A.; Van Meurs, Joyce B J; Romieu, Isabelle; Arnett, Donna K.; Ong, Ken K.; Liu, Yongmei; Waldenberger, Melanie; Deary, Ian J.; Fornage, Myriam; Levy, Daniel; London, Stephanie J.

In: Circulation: Cardiovascular Genetics, Vol. 9, No. 5, 01.10.2016, p. 436-447.

Research output: Contribution to journalArticle

Joehanes, R, Just, AC, Marioni, RE, Pilling, LC, Reynolds, LM, Mandaviya, PR, Guan, W, Xu, T, Elks, CE, Aslibekyan, S, Moreno-Macias, H, Smith, JA, Brody, JA, Dhingra, R, Yousefi, P, Pankow, JS, Kunze, S, Shah, SH, McRae, AF, Lohman, K, Sha, J, Absher, DM, Ferrucci, L, Zhao, W, Demerath, EW, Bressler, J, Grove, ML, Huan, T, Liu, C, Mendelson, MM, Yao, C, Kiel, DP, Peters, A, Wang-Sattler, R, Visscher, PM, Wray, NR, Starr, JM, Ding, J, Rodriguez, CJ, Wareham, NJ, Irvin, MR, Zhi, D, Barrdahl, M, Vineis, P, Ambatipudi, S, Uitterlinden, AG, Hofman, A, Schwartz, J, Colicino, E, Hou, L, Vokonas, PS, Hernandez, DG, Singleton, AB, Bandinelli, S, Turner, ST, Ware, EB, Smith, AK, Klengel, T, Binder, EB, Psaty, BM, Taylor, KD, Gharib, SA, Swenson, BR, Liang, L, Demeo, DL, O'Connor, GT, Herceg, Z, Ressler, KJ, Conneely, KN, Sotoodehnia, N, Kardia, SLR, Melzer, D, Baccarelli, AA, Van Meurs, JBJ, Romieu, I, Arnett, DK, Ong, KK, Liu, Y, Waldenberger, M, Deary, IJ, Fornage, M, Levy, D & London, SJ 2016, 'Epigenetic Signatures of Cigarette Smoking', Circulation: Cardiovascular Genetics, vol. 9, no. 5, pp. 436-447. https://doi.org/10.1161/CIRCGENETICS.116.001506
Joehanes R, Just AC, Marioni RE, Pilling LC, Reynolds LM, Mandaviya PR et al. Epigenetic Signatures of Cigarette Smoking. Circulation: Cardiovascular Genetics. 2016 Oct 1;9(5):436-447. https://doi.org/10.1161/CIRCGENETICS.116.001506
Joehanes, Roby ; Just, Allan C. ; Marioni, Riccardo E. ; Pilling, Luke C. ; Reynolds, Lindsay M. ; Mandaviya, Pooja R. ; Guan, Weihua ; Xu, Tao ; Elks, Cathy E. ; Aslibekyan, Stella ; Moreno-Macias, Hortensia ; Smith, Jennifer A. ; Brody, Jennifer A. ; Dhingra, Radhika ; Yousefi, Paul ; Pankow, James S. ; Kunze, Sonja ; Shah, Sonia H. ; McRae, Allan F. ; Lohman, Kurt ; Sha, Jin ; Absher, Devin M. ; Ferrucci, Luigi ; Zhao, Wei ; Demerath, Ellen W. ; Bressler, Jan ; Grove, Megan L. ; Huan, Tianxiao ; Liu, Chunyu ; Mendelson, Michael M. ; Yao, Chen ; Kiel, Douglas P. ; Peters, Annette ; Wang-Sattler, Rui ; Visscher, Peter M. ; Wray, Naomi R. ; Starr, John M. ; Ding, Jingzhong ; Rodriguez, Carlos J. ; Wareham, Nicholas J. ; Irvin, Marguerite R. ; Zhi, Degui ; Barrdahl, Myrto ; Vineis, Paolo ; Ambatipudi, Srikant ; Uitterlinden, André G. ; Hofman, Albert ; Schwartz, Joel ; Colicino, Elena ; Hou, Lifang ; Vokonas, Pantel S. ; Hernandez, Dena G. ; Singleton, Andrew B. ; Bandinelli, Stefania ; Turner, Stephen T ; Ware, Erin B. ; Smith, Alicia K. ; Klengel, Torsten ; Binder, Elisabeth B. ; Psaty, Bruce M. ; Taylor, Kent D. ; Gharib, Sina A. ; Swenson, Brenton R. ; Liang, Liming ; Demeo, Dawn L. ; O'Connor, George T. ; Herceg, Zdenko ; Ressler, Kerry J. ; Conneely, Karen N. ; Sotoodehnia, Nona ; Kardia, Sharon L R ; Melzer, David ; Baccarelli, Andrea A. ; Van Meurs, Joyce B J ; Romieu, Isabelle ; Arnett, Donna K. ; Ong, Ken K. ; Liu, Yongmei ; Waldenberger, Melanie ; Deary, Ian J. ; Fornage, Myriam ; Levy, Daniel ; London, Stephanie J. / Epigenetic Signatures of Cigarette Smoking. In: Circulation: Cardiovascular Genetics. 2016 ; Vol. 9, No. 5. pp. 436-447.
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T1 - Epigenetic Signatures of Cigarette Smoking

AU - Joehanes, Roby

AU - Just, Allan C.

AU - Marioni, Riccardo E.

AU - Pilling, Luke C.

AU - Reynolds, Lindsay M.

AU - Mandaviya, Pooja R.

AU - Guan, Weihua

AU - Xu, Tao

AU - Elks, Cathy E.

AU - Aslibekyan, Stella

AU - Moreno-Macias, Hortensia

AU - Smith, Jennifer A.

AU - Brody, Jennifer A.

AU - Dhingra, Radhika

AU - Yousefi, Paul

AU - Pankow, James S.

AU - Kunze, Sonja

AU - Shah, Sonia H.

AU - McRae, Allan F.

AU - Lohman, Kurt

AU - Sha, Jin

AU - Absher, Devin M.

AU - Ferrucci, Luigi

AU - Zhao, Wei

AU - Demerath, Ellen W.

AU - Bressler, Jan

AU - Grove, Megan L.

AU - Huan, Tianxiao

AU - Liu, Chunyu

AU - Mendelson, Michael M.

AU - Yao, Chen

AU - Kiel, Douglas P.

AU - Peters, Annette

AU - Wang-Sattler, Rui

AU - Visscher, Peter M.

AU - Wray, Naomi R.

AU - Starr, John M.

AU - Ding, Jingzhong

AU - Rodriguez, Carlos J.

AU - Wareham, Nicholas J.

AU - Irvin, Marguerite R.

AU - Zhi, Degui

AU - Barrdahl, Myrto

AU - Vineis, Paolo

AU - Ambatipudi, Srikant

AU - Uitterlinden, André G.

AU - Hofman, Albert

AU - Schwartz, Joel

AU - Colicino, Elena

AU - Hou, Lifang

AU - Vokonas, Pantel S.

AU - Hernandez, Dena G.

AU - Singleton, Andrew B.

AU - Bandinelli, Stefania

AU - Turner, Stephen T

AU - Ware, Erin B.

AU - Smith, Alicia K.

AU - Klengel, Torsten

AU - Binder, Elisabeth B.

AU - Psaty, Bruce M.

AU - Taylor, Kent D.

AU - Gharib, Sina A.

AU - Swenson, Brenton R.

AU - Liang, Liming

AU - Demeo, Dawn L.

AU - O'Connor, George T.

AU - Herceg, Zdenko

AU - Ressler, Kerry J.

AU - Conneely, Karen N.

AU - Sotoodehnia, Nona

AU - Kardia, Sharon L R

AU - Melzer, David

AU - Baccarelli, Andrea A.

AU - Van Meurs, Joyce B J

AU - Romieu, Isabelle

AU - Arnett, Donna K.

AU - Ong, Ken K.

AU - Liu, Yongmei

AU - Waldenberger, Melanie

AU - Deary, Ian J.

AU - Fornage, Myriam

AU - Levy, Daniel

AU - London, Stephanie J.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Background-DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results-To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10-7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10-7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions-Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

AB - Background-DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results-To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10-7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10-7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions-Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

KW - biomarkers

KW - genome-wide association study

KW - meta-analysis

KW - methylation

KW - smoking

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