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Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

Phuwanat Sakornsakolpat, Dmitry Prokopenko, Maxime Lamontagne, Nicola F. Reeve, Anna L. Guyatt, Victoria E. Jackson, Nick Shrine, Dandi Qiao, Traci M. Bartz, Deog Kyeom Kim, Mi Kyeong Lee, Jeanne C. Latourelle, Xingnan Li, Jarrett D. Morrow, Ma’en Obeidat, Annah B. Wyss, Xiaobo Zhou, Per Bakke, R Graham Barr, Terri H. Beaty, Steven A. Belinsky, Guy G. Brusselle, James D. Crapo, Kim de Jong, Dawn L. DeMeo, Tasha E. Fingerlin, Sina A. Gharib, Amund Gulsvik, Ian P. Hall, John E. Hokanson, Woo Jin Kim, David A. Lomas, Stephanie J. London, Deborah A. Meyers, George T. O’Connor, Stephen I. Rennard, David A. Schwartz, Pawel Sliwinski, David Sparrow, David P. Strachan, Ruth Tal-Singer, Yohannes Tesfaigzi, Jørgen Vestbo, Judith M. Vonk, Jae-Joon Yim, Yohan Bossé, Ani Manichaikul, Lies Lahousse, Edwin K. Silverman, H. Marike Boezen, Louise V. Wain, Martin D. Tobin, Brian D. Hobbs, Michael H. Cho, International COPD Genetics Consortium
doi: https://doi.org/10.1101/355644
Phuwanat Sakornsakolpat
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
2Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Dmitry Prokopenko
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Maxime Lamontagne
3Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada
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Nicola F. Reeve
4Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
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Anna L. Guyatt
4Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
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Victoria E. Jackson
4Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
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Nick Shrine
4Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
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Dandi Qiao
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Traci M. Bartz
5Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
6Department of Medicine, University of Washington, Seattle, WA, USA
7Department of Biostatistics, University of Washington, Seattle, WA, USA
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Deog Kyeom Kim
8Seoul National University College of Medicine, SMG-SNU Boramae Medical Center, Seoul, South Korea
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Mi Kyeong Lee
9Department of Internal Medicine and Environmental Health Center, School of Medicine, Kangwon National University, Chuncheon, South Korea
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Jeanne C. Latourelle
10Department of Neurology, Boston University School of Medicine, Boston, MA, USA
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Xingnan Li
11Department of Medicine, University of Arizona, Tuscson, AZ
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Jarrett D. Morrow
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Ma’en Obeidat
12The University of British Columbia Center for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada
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Annah B. Wyss
13Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA
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Xiaobo Zhou
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Per Bakke
14Department of Clinical Science, University of Bergen, Bergen, Norway
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R Graham Barr
15Department of Medicine, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
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Terri H. Beaty
16Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
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Steven A. Belinsky
17Lovelace Respiratory Research Institute, Albuquerque, NM, USA
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Guy G. Brusselle
18Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
19Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
20Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
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James D. Crapo
21Department of Medicine, Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA
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Kim de Jong
22University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands
23University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands
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Dawn L. DeMeo
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
24Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Tasha E. Fingerlin
25Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
26Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA
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Sina A. Gharib
27Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, WA, USA
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Amund Gulsvik
14Department of Clinical Science, University of Bergen, Bergen, Norway
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Ian P. Hall
28Division of Respiratory Medicine, Queen’s Medical Centre, University of Nottingham, Nottingham, UK
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John E. Hokanson
29Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Woo Jin Kim
9Department of Internal Medicine and Environmental Health Center, School of Medicine, Kangwon National University, Chuncheon, South Korea
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David A. Lomas
30University College London, London, UK
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Stephanie J. London
13Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA
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Deborah A. Meyers
11Department of Medicine, University of Arizona, Tuscson, AZ
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George T. O’Connor
31The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA
32Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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Stephen I. Rennard
33Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
34Clinical Discovery Unit, AstraZeneca, Cambridge, UK
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David A. Schwartz
25Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
35Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA
36Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, CO, USA
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Pawel Sliwinski
372nd Department of Respiratory Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
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David Sparrow
38VA Boston Healthcare System and Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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David P. Strachan
39Population Health Research Institute, St. George’s University of London, London, UK
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Ruth Tal-Singer
40GSK R&D, King of Prussia, PA, USA
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Yohannes Tesfaigzi
17Lovelace Respiratory Research Institute, Albuquerque, NM, USA
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Jørgen Vestbo
41School of Biological Sciences, University of Manchester, Manchester, UK
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Judith M. Vonk
22University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands
23University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands
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Jae-Joon Yim
42Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
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Yohan Bossé
3Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada
43Department of Molecular Medicine, Laval University, Québec, Canada
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Ani Manichaikul
44Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
45Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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Lies Lahousse
46Department of Bioanalysis, Ghent University, Ghent, Belgium
18Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
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Edwin K. Silverman
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
24Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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H. Marike Boezen
22University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands
23University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands
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Louise V. Wain
4Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
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Martin D. Tobin
4Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
47National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK
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Brian D. Hobbs
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
24Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Michael H. Cho
1Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
24Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Summary

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5×10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

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Posted June 26, 2018.
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Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations
Phuwanat Sakornsakolpat, Dmitry Prokopenko, Maxime Lamontagne, Nicola F. Reeve, Anna L. Guyatt, Victoria E. Jackson, Nick Shrine, Dandi Qiao, Traci M. Bartz, Deog Kyeom Kim, Mi Kyeong Lee, Jeanne C. Latourelle, Xingnan Li, Jarrett D. Morrow, Ma’en Obeidat, Annah B. Wyss, Xiaobo Zhou, Per Bakke, R Graham Barr, Terri H. Beaty, Steven A. Belinsky, Guy G. Brusselle, James D. Crapo, Kim de Jong, Dawn L. DeMeo, Tasha E. Fingerlin, Sina A. Gharib, Amund Gulsvik, Ian P. Hall, John E. Hokanson, Woo Jin Kim, David A. Lomas, Stephanie J. London, Deborah A. Meyers, George T. O’Connor, Stephen I. Rennard, David A. Schwartz, Pawel Sliwinski, David Sparrow, David P. Strachan, Ruth Tal-Singer, Yohannes Tesfaigzi, Jørgen Vestbo, Judith M. Vonk, Jae-Joon Yim, Yohan Bossé, Ani Manichaikul, Lies Lahousse, Edwin K. Silverman, H. Marike Boezen, Louise V. Wain, Martin D. Tobin, Brian D. Hobbs, Michael H. Cho, International COPD Genetics Consortium
bioRxiv 355644; doi: https://doi.org/10.1101/355644
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Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations
Phuwanat Sakornsakolpat, Dmitry Prokopenko, Maxime Lamontagne, Nicola F. Reeve, Anna L. Guyatt, Victoria E. Jackson, Nick Shrine, Dandi Qiao, Traci M. Bartz, Deog Kyeom Kim, Mi Kyeong Lee, Jeanne C. Latourelle, Xingnan Li, Jarrett D. Morrow, Ma’en Obeidat, Annah B. Wyss, Xiaobo Zhou, Per Bakke, R Graham Barr, Terri H. Beaty, Steven A. Belinsky, Guy G. Brusselle, James D. Crapo, Kim de Jong, Dawn L. DeMeo, Tasha E. Fingerlin, Sina A. Gharib, Amund Gulsvik, Ian P. Hall, John E. Hokanson, Woo Jin Kim, David A. Lomas, Stephanie J. London, Deborah A. Meyers, George T. O’Connor, Stephen I. Rennard, David A. Schwartz, Pawel Sliwinski, David Sparrow, David P. Strachan, Ruth Tal-Singer, Yohannes Tesfaigzi, Jørgen Vestbo, Judith M. Vonk, Jae-Joon Yim, Yohan Bossé, Ani Manichaikul, Lies Lahousse, Edwin K. Silverman, H. Marike Boezen, Louise V. Wain, Martin D. Tobin, Brian D. Hobbs, Michael H. Cho, International COPD Genetics Consortium
bioRxiv 355644; doi: https://doi.org/10.1101/355644

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