Ma'en Obeidat1, Ke Hao2, Yohan Bossé3, David C Nickle4, Yunlong Nie1, Dirkje S Postma5, Michel Laviolette6, Andrew J Sandford7, Denise D Daley7, James C Hogg8, W Mark Elliott8, Nick Fishbane1, Wim Timens9, Pirro G Hysi10, Jaakko Kaprio11, James F Wilson12, Jennie Hui13, Rajesh Rawal14, Holger Schulz15, Beate Stubbe16, Caroline Hayward17, Ozren Polasek18, Marjo-Riitta Järvelin19, Jing Hua Zhao20, Deborah Jarvis21, Mika Kähönen22, Nora Franceschini23, Kari E North24, Daan W Loth25, Guy G Brusselle26, Albert Vernon Smith27, Vilmundur Gudnason27, Traci M Bartz28, Jemma B Wilk29, George T O'Connor30, Patricia A Cassano31, Wenbo Tang32, Louise V Wain33, María Soler Artigas33, Sina A Gharib34, David P Strachan35, Don D Sin7, Martin D Tobin33, Stephanie J London36, Ian P Hall37, Peter D Paré38. 1. University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada. 2. Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3. Department of Molecular Medicine, Laval University, Québec, QC, Canada; Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, QC, Canada. 4. Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, MA, USA. 5. University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, Netherlands. 6. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, QC, Canada. 7. University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada; Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. 8. University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. 9. Department of Pathology and Medical Biology, GRIAC Research Institute, University of Groningen, Groningen, Netherlands. 10. Department of Twin Research and Genetic Epidemiology, King's College, London, UK. 11. Department of Public Health, and Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland. 12. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. 13. Busselton Population Medical Research Institute, Busselton, WA, Australia; PathWest Laboratory Medicine of Western Australia, Nedlands, WA, Australia; School of Population Health and School of Pahology and Laboratory Medicine, University of Western Australia, Nedlands, WA, Australia. 14. Research Unit of Molecular Epidemiology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Genetic Epidemiology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 15. Institute of Epidemiology I, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany. 16. University Hospital, Department of Internal Medicine B, Greifswald, Germany. 17. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. 18. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK; Faculty of Medicine, University of Split, Croatia. 19. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College, London, UK; Center for Life Course Epidemiology, Faculty of Medicine, Biocenter Oulu, and Unit of Primary Care, Oulu University Hospital, University of Oulu, Oulu, Finland. 20. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge UK. 21. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College, London, UK; Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College, London, UK. 22. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland. 23. Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA. 24. Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; University of North Carolina Center for Genome Sciences, Chapel Hill, NC, USA. 25. Departments of Epidemiology and Respiratory Medicine, Erasmus MC, Rotterdam, Netherlands. 26. Departments of Epidemiology and Respiratory Medicine, Erasmus MC, Rotterdam, Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. 27. Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 28. Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA. 29. Human Genetics & Computational Biomedicine, Pfizer Worldwide Research and Development, Cambridge, MA, USA. 30. Pulmonary Center, Boston University School of Medicine, Boston, MA, USA; NHLBI Framingham Heart Study, Framingham, MA, USA. 31. Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medical College, NY, USA. 32. Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA. 33. University of Leicester, Genetic Epidemiology Group, Department of Health Sciences, Leicester, UK; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK. 34. Computational Medicine Core, Center for Lung Biology, University of Washington, Seattle, WA, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA. 35. Population Health Research Institute, St George's, University of London, London, UK. 36. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA. 37. University of Nottingham Division of Respiratory Medicine, University Hospital of Nottingham, Nottingham, UK. 38. University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada; Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: peter.pare@hli.ubc.ca.
Abstract
BACKGROUND: Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48,201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. METHODS: The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. FINDINGS: SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. INTERPRETATION: The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico. FUNDING: The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.
BACKGROUND: Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48,201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. METHODS: The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. FINDINGS: SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. INTERPRETATION: The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico. FUNDING: The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.
Authors: Lucia A Hindorff; Praveen Sethupathy; Heather A Junkins; Erin M Ramos; Jayashri P Mehta; Francis S Collins; Teri A Manolio Journal: Proc Natl Acad Sci U S A Date: 2009-05-27 Impact factor: 11.205
Authors: Megan Hardin; Jan Zielinski; Emily S Wan; Craig P Hersh; Peter J Castaldi; Eric Schwinder; Iwona Hawrylkiewicz; Pawel Sliwinski; Michael H Cho; Edwin K Silverman Journal: Am J Respir Cell Mol Biol Date: 2012-03-29 Impact factor: 6.914
Authors: Peter J Castaldi; Michael H Cho; Xiaobo Zhou; Weiliang Qiu; Michael Mcgeachie; Bartolome Celli; Per Bakke; Amund Gulsvik; David A Lomas; James D Crapo; Terri H Beaty; Stephen Rennard; Benjamin Harshfield; Christoph Lange; Dave Singh; Ruth Tal-Singer; John H Riley; John Quackenbush; Benjamin A Raby; Vincent J Carey; Edwin K Silverman; Craig P Hersh Journal: Hum Mol Genet Date: 2014-10-14 Impact factor: 6.150
Authors: Akkelies E Dijkstra; Joanna Smolonska; Maarten van den Berge; Ciska Wijmenga; Pieter Zanen; Marjan A Luinge; Mathieu Platteel; Jan-Willem Lammers; Magnus Dahlback; Kerrie Tosh; Pieter S Hiemstra; Peter J Sterk; Avi Spira; Jorgen Vestbo; Borge G Nordestgaard; Marianne Benn; Sune F Nielsen; Morten Dahl; W Monique Verschuren; H Susan J Picavet; Henriette A Smit; Michael Owsijewitsch; Hans U Kauczor; Harry J de Koning; Eva Nizankowska-Mogilnicka; Filip Mejza; Pawel Nastalek; Cleo C van Diemen; Michael H Cho; Edwin K Silverman; James D Crapo; Terri H Beaty; David A Lomas; Per Bakke; Amund Gulsvik; Yohan Bossé; Ma'en Obeidat; M A Obeidat; Daan W Loth; Lies Lahousse; Fernando Rivadeneira; Andre G Uitterlinden; Andre Hofman; Bruno H Stricker; Guy G Brusselle; Cornelia M van Duijn; Uilke Brouwer; Gerard H Koppelman; Judith M Vonk; Martijn C Nawijn; Harry J M Groen; Wim Timens; H Marike Boezen; Dirkje S Postma Journal: PLoS One Date: 2014-04-08 Impact factor: 3.240
Authors: Joshua D Campbell; John E McDonough; Julie E Zeskind; Tillie L Hackett; Dmitri V Pechkovsky; Corry-Anke Brandsma; Masaru Suzuki; John V Gosselink; Gang Liu; Yuriy O Alekseyev; Ji Xiao; Xiaohui Zhang; Shizu Hayashi; Joel D Cooper; Wim Timens; Dirkje S Postma; Darryl A Knight; Marc E Lenburg; James C Hogg; Avrum Spira Journal: Genome Med Date: 2012-08-31 Impact factor: 11.117
Authors: Maxime Lamontagne; Jean-Christophe Bérubé; Ma'en Obeidat; Michael H Cho; Brian D Hobbs; Phuwanat Sakornsakolpat; Kim de Jong; H Marike Boezen; David Nickle; Ke Hao; Wim Timens; Maarten van den Berge; Philippe Joubert; Michel Laviolette; Don D Sin; Peter D Paré; Yohan Bossé Journal: Hum Mol Genet Date: 2018-05-15 Impact factor: 6.150
Authors: M Arfan Ikram; Guy G O Brusselle; Sarwa Darwish Murad; Cornelia M van Duijn; Oscar H Franco; André Goedegebure; Caroline C W Klaver; Tamar E C Nijsten; Robin P Peeters; Bruno H Stricker; Henning Tiemeier; André G Uitterlinden; Meike W Vernooij; Albert Hofman Journal: Eur J Epidemiol Date: 2017-10-24 Impact factor: 8.082
Authors: Ma'en Obeidat; Yunlong Nie; Nick Fishbane; Xuan Li; Yohan Bossé; Philippe Joubert; David C Nickle; Ke Hao; Dirkje S Postma; Wim Timens; Marc A Sze; Casey P Shannon; Zsuzsanna Hollander; Raymond T Ng; Bruce McManus; Bruce E Miller; Stephen Rennard; Avrum Spira; Tillie-Louise Hackett; Wan Lam; Stephen Lam; Rosa Faner; Alvar Agusti; James C Hogg; Don D Sin; Peter D Paré Journal: Am J Respir Cell Mol Biol Date: 2017-10 Impact factor: 6.914
Authors: Juan Jose Carmona; Richard T Barfield; Tommaso Panni; Jamaji C Nwanaji-Enwerem; Allan C Just; John N Hutchinson; Elena Colicino; Stefan Karrasch; Simone Wahl; Sonja Kunze; Nadereh Jafari; Yinan Zheng; Lifang Hou; Dawn L DeMeo; Augusto A Litonjua; Pantel S Vokonas; Annette Peters; Xihong Lin; Joel Schwartz; Holger Schulz; Andrea A Baccarelli Journal: Epigenetics Date: 2018-10-21 Impact factor: 4.528
Authors: Anneli C S Bolund; Anna Starnawska; Martin R Miller; Vivi Schlünssen; Vibeke Backer; Anders D Børglum; Kaare Christensen; Qihua Tan; Lene Christiansen; Torben Sigsgaard Journal: Clin Epigenetics Date: 2017-12-21 Impact factor: 6.551
Authors: Jarrett D Morrow; Xiaobo Zhou; Taotao Lao; Zhiqiang Jiang; Dawn L DeMeo; Michael H Cho; Weiliang Qiu; Suzanne Cloonan; Victor Pinto-Plata; Bartholome Celli; Nathaniel Marchetti; Gerard J Criner; Raphael Bueno; George R Washko; Kimberly Glass; John Quackenbush; Augustine M K Choi; Edwin K Silverman; Craig P Hersh Journal: Sci Rep Date: 2017-03-13 Impact factor: 4.379
Authors: Louise V Wain; Nick Shrine; María Soler Artigas; A Mesut Erzurumluoglu; Boris Noyvert; Lara Bossini-Castillo; Ma'en Obeidat; Amanda P Henry; Michael A Portelli; Robert J Hall; Charlotte K Billington; Tracy L Rimington; Anthony G Fenech; Catherine John; Tineka Blake; Victoria E Jackson; Richard J Allen; Bram P Prins; Archie Campbell; David J Porteous; Marjo-Riitta Jarvelin; Matthias Wielscher; Alan L James; Jennie Hui; Nicholas J Wareham; Jing Hua Zhao; James F Wilson; Peter K Joshi; Beate Stubbe; Rajesh Rawal; Holger Schulz; Medea Imboden; Nicole M Probst-Hensch; Stefan Karrasch; Christian Gieger; Ian J Deary; Sarah E Harris; Jonathan Marten; Igor Rudan; Stefan Enroth; Ulf Gyllensten; Shona M Kerr; Ozren Polasek; Mika Kähönen; Ida Surakka; Veronique Vitart; Caroline Hayward; Terho Lehtimäki; Olli T Raitakari; David M Evans; A John Henderson; Craig E Pennell; Carol A Wang; Peter D Sly; Emily S Wan; Robert Busch; Brian D Hobbs; Augusto A Litonjua; David W Sparrow; Amund Gulsvik; Per S Bakke; James D Crapo; Terri H Beaty; Nadia N Hansel; Rasika A Mathias; Ingo Ruczinski; Kathleen C Barnes; Yohan Bossé; Philippe Joubert; Maarten van den Berge; Corry-Anke Brandsma; Peter D Paré; Don D Sin; David C Nickle; Ke Hao; Omri Gottesman; Frederick E Dewey; Shannon E Bruse; David J Carey; H Lester Kirchner; Stefan Jonsson; Gudmar Thorleifsson; Ingileif Jonsdottir; Thorarinn Gislason; Kari Stefansson; Claudia Schurmann; Girish Nadkarni; Erwin P Bottinger; Ruth J F Loos; Robin G Walters; Zhengming Chen; Iona Y Millwood; Julien Vaucher; Om P Kurmi; Liming Li; Anna L Hansell; Chris Brightling; Eleftheria Zeggini; Michael H Cho; Edwin K Silverman; Ian Sayers; Gosia Trynka; Andrew P Morris; David P Strachan; Ian P Hall; Martin D Tobin Journal: Nat Genet Date: 2017-02-06 Impact factor: 38.330