Epigenetic Signatures of Cigarette Smoking
Authors: 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. 
Published: September 2016

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.