Chen Yao1,2, Roby Joehanes1,2, Rory Wilson3,4, Toshiko Tanaka5, Luigi Ferrucci5, Anja Kretschmer3,4, Holger Prokisch6,7,8, Katharina Schramm9,10,11, Christian Gieger3,4, Annette Peters3,4,12, Melanie Waldenberger3,4,12, Carola Marzi13, Christian Herder14,15,16, Daniel Levy17,18. 1. The Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA, 01702, USA. 2. The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. 3. Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Bavaria, Neuherberg, Germany. 4. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Bavaria, Neuherberg, Germany. 5. Longitudinal Study Section, National Institute On Aging, Baltimore, MD, USA. 6. Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. 7. Institute of Human Genetics, Technical University Munich, München, Germany. 8. Institute for Neurogenomics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. 9. Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg, Germany. 10. Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, 81377, Munich, Germany. 11. Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, 81377, Munich, Germany. 12. German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. 13. Research Unit of Molecular Epidemiology, Institute of Epidemiology II, German Research Center for Environmental Health, Neuherberg, Germany. 14. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research At Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 15. German Center for Diabetes Research (DZD), Partner Düsseldorf, Germany. 16. Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. 17. The Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA, 01702, USA. levyd@nih.gov. 18. The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. levyd@nih.gov.
Abstract
BACKGROUND: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. RESULTS: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. CONCLUSIONS: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
BACKGROUND: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. RESULTS: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. CONCLUSIONS: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
Authors: Adiv A Johnson; Kemal Akman; Stuart R G Calimport; Daniel Wuttke; Alexandra Stolzing; João Pedro de Magalhães Journal: Rejuvenation Res Date: 2012-10 Impact factor: 4.663
Authors: Joaquim Radua; André Schmidt; Stefan Borgwardt; Andreas Heinz; Florian Schlagenhauf; Philip McGuire; Paolo Fusar-Poli Journal: JAMA Psychiatry Date: 2015-12 Impact factor: 21.596
Authors: Jennifer Kriebel; Christian Herder; Wolfgang Rathmann; Simone Wahl; Sonja Kunze; Sophie Molnos; Nadezda Volkova; Katharina Schramm; Maren Carstensen-Kirberg; Melanie Waldenberger; Christian Gieger; Annette Peters; Thomas Illig; Holger Prokisch; Michael Roden; Harald Grallert Journal: PLoS One Date: 2016-03-28 Impact factor: 3.240
Authors: Charles E Breeze; Dirk S Paul; Jenny van Dongen; Lee M Butcher; John C Ambrose; James E Barrett; Robert Lowe; Vardhman K Rakyan; Valentina Iotchkova; Mattia Frontini; Kate Downes; Willem H Ouwehand; Jonathan Laperle; Pierre-Étienne Jacques; Guillaume Bourque; Anke K Bergmann; Reiner Siebert; Edo Vellenga; Sadia Saeed; Filomena Matarese; Joost H A Martens; Hendrik G Stunnenberg; Andrew E Teschendorff; Javier Herrero; Ewan Birney; Ian Dunham; Stephan Beck Journal: Cell Rep Date: 2016-11-15 Impact factor: 9.423
Authors: Simone Wahl; Alexander Drong; Benjamin Lehne; Marie Loh; William R Scott; Sonja Kunze; Pei-Chien Tsai; Janina S Ried; Weihua Zhang; Youwen Yang; Sili Tan; Giovanni Fiorito; Lude Franke; Simonetta Guarrera; Silva Kasela; Jennifer Kriebel; Rebecca C Richmond; Marco Adamo; Uzma Afzal; Mika Ala-Korpela; Benedetta Albetti; Ole Ammerpohl; Jane F Apperley; Marian Beekman; Pier Alberto Bertazzi; S Lucas Black; Christine Blancher; Marc-Jan Bonder; Mario Brosch; Maren Carstensen-Kirberg; Anton J M de Craen; Simon de Lusignan; Abbas Dehghan; Mohamed Elkalaawy; Krista Fischer; Oscar H Franco; Tom R Gaunt; Jochen Hampe; Majid Hashemi; Aaron Isaacs; Andrew Jenkinson; Sujeet Jha; Norihiro Kato; Vittorio Krogh; Michael Laffan; Christa Meisinger; Thomas Meitinger; Zuan Yu Mok; Valeria Motta; Hong Kiat Ng; Zacharoula Nikolakopoulou; Georgios Nteliopoulos; Salvatore Panico; Natalia Pervjakova; Holger Prokisch; Wolfgang Rathmann; Michael Roden; Federica Rota; Michelle Ann Rozario; Johanna K Sandling; Clemens Schafmayer; Katharina Schramm; Reiner Siebert; P Eline Slagboom; Pasi Soininen; Lisette Stolk; Konstantin Strauch; E-Shyong Tai; Letizia Tarantini; Barbara Thorand; Ettje F Tigchelaar; Rosario Tumino; Andre G Uitterlinden; Cornelia van Duijn; Joyce B J van Meurs; Paolo Vineis; Ananda Rajitha Wickremasinghe; Cisca Wijmenga; Tsun-Po Yang; Wei Yuan; Alexandra Zhernakova; Rachel L Batterham; George Davey Smith; Panos Deloukas; Bastiaan T Heijmans; Christian Herder; Albert Hofman; Cecilia M Lindgren; Lili Milani; Pim van der Harst; Annette Peters; Thomas Illig; Caroline L Relton; Melanie Waldenberger; Marjo-Riitta Järvelin; Valentina Bollati; Richie Soong; Tim D Spector; James Scott; Mark I McCarthy; Paul Elliott; Jordana T Bell; Giuseppe Matullo; Christian Gieger; Jaspal S Kooner; Harald Grallert; John C Chambers Journal: Nature Date: 2016-12-21 Impact factor: 49.962
Authors: Sonja Zeilinger; Brigitte Kühnel; Norman Klopp; Hansjörg Baurecht; Anja Kleinschmidt; Christian Gieger; Stephan Weidinger; Eva Lattka; Jerzy Adamski; Annette Peters; Konstantin Strauch; Melanie Waldenberger; Thomas Illig Journal: PLoS One Date: 2013-05-17 Impact factor: 3.240
Authors: Eugene Andres Houseman; William P Accomando; Devin C Koestler; Brock C Christensen; Carmen J Marsit; Heather H Nelson; John K Wiencke; Karl T Kelsey Journal: BMC Bioinformatics Date: 2012-05-08 Impact factor: 3.169
Authors: Yinan Zheng; Brian T Joyce; Shih-Jen Hwang; Jiantao Ma; Lei Liu; Norrina B Allen; Amy E Krefman; Jun Wang; Tao Gao; Drew R Nannini; Haixiang Zhang; David R Jacobs; Myron D Gross; Myriam Fornage; Cora E Lewis; Pamela J Schreiner; Stephen Sidney; Dongquan Chen; Philip Greenland; Daniel Levy; Lifang Hou; Donald M Lloyd-Jones Journal: Circulation Date: 2022-06-02 Impact factor: 39.918
Authors: Matthias Wielscher; Pooja R Mandaviya; Brigitte Kuehnel; Roby Joehanes; Rima Mustafa; Oliver Robinson; Yan Zhang; Barbara Bodinier; Esther Walton; Pashupati P Mishra; Pascal Schlosser; Rory Wilson; Pei-Chien Tsai; Saranya Palaniswamy; Riccardo E Marioni; Giovanni Fiorito; Giovanni Cugliari; Ville Karhunen; Mohsen Ghanbari; Bruce M Psaty; Marie Loh; Joshua C Bis; Benjamin Lehne; Nona Sotoodehnia; Ian J Deary; Marc Chadeau-Hyam; Jennifer A Brody; Alexia Cardona; Elizabeth Selvin; Alicia K Smith; Andrew H Miller; Mylin A Torres; Eirini Marouli; Xin Gào; Joyce B J van Meurs; Johanna Graf-Schindler; Wolfgang Rathmann; Wolfgang Koenig; Annette Peters; Wolfgang Weninger; Matthias Farlik; Tao Zhang; Wei Chen; Yujing Xia; Alexander Teumer; Matthias Nauck; Hans J Grabe; Macus Doerr; Terho Lehtimäki; Weihua Guan; Lili Milani; Toshiko Tanaka; Krista Fisher; Lindsay L Waite; Silva Kasela; Paolo Vineis; Niek Verweij; Pim van der Harst; Licia Iacoviello; Carlotta Sacerdote; Salvatore Panico; Vittorio Krogh; Rosario Tumino; Evangelia Tzala; Giuseppe Matullo; Mikko A Hurme; Olli T Raitakari; Elena Colicino; Andrea A Baccarelli; Mika Kähönen; Karl-Heinz Herzig; Shengxu Li; Karen N Conneely; Jaspal S Kooner; Anna Köttgen; Bastiaan T Heijmans; Panos Deloukas; Caroline Relton; Ken K Ong; Jordana T Bell; Eric Boerwinkle; Paul Elliott; Hermann Brenner; Marian Beekman; Daniel Levy; Melanie Waldenberger; John C Chambers; Abbas Dehghan; Marjo-Riitta Järvelin Journal: Nat Commun Date: 2022-05-03 Impact factor: 17.694