Meta-Analysis

. 2023 Mar;55(3):410-422.

doi: 10.1038/s41588-023-01314-0. Epub 2023 Mar 13.

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Nick Shrine^#¹, Abril G Izquierdo^#², Jing Chen^#², Richard Packer^#², Robert J Hall³, Anna L Guyatt², Chiara Batini^{2

4}, Rebecca J Thompson³, Chandan Pavuluri⁵, Vidhi Malik⁵, Brian D Hobbs^{5

6}, Matthew Moll⁵, Wonji Kim⁵, Ruth Tal-Singer⁷, Per Bakke⁸, Katherine A Fawcett², Catherine John^{2

4}, Kayesha Coley², Noemi Nicole Piga², Alfred Pozarickij⁹, Kuang Lin⁹, Iona Y Millwood^{9

10}, Zhengming Chen^{9

10}, Liming Li¹¹; China Kadoorie Biobank Collaborative Group; Sara R A Wijnant^{12

13

14}, Lies Lahousse^{13

14}, Guy Brusselle^{12

14}, Andre G Uitterlinden¹⁵, Ani Manichaikul¹⁶, Elizabeth C Oelsner¹⁷, Stephen S Rich¹⁶, R Graham Barr¹⁷, Shona M Kerr¹⁸, Veronique Vitart¹⁸, Michael R Brown¹⁹, Matthias Wielscher²⁰, Medea Imboden^{21

22}, Ayoung Jeong^{21

22}, Traci M Bartz²³, Sina A Gharib²⁴, Claudia Flexeder^{25

26

27}, Stefan Karrasch^{25

26

27}, Christian Gieger^{27

28}, Annette Peters^{27

29}, Beate Stubbe³⁰, Xiaowei Hu¹⁶, Victor E Ortega³¹, Deborah A Meyers³², Eugene R Bleecker³², Stacey B Gabriel³³, Namrata Gupta³³, Albert Vernon Smith^{34

35}, Jian'an Luan³⁶, Jing-Hua Zhao³⁷, Ailin F Hansen³⁸, Arnulf Langhammer^{39

40}, Cristen Willer^{41

42

43}, Laxmi Bhatta³⁸, David Porteous⁴⁴, Blair H Smith⁴⁵, Archie Campbell⁴⁴, Tamar Sofer^{46

47

48}, Jiwon Lee⁴⁶, Martha L Daviglus⁴⁹, Bing Yu⁵⁰, Elise Lim⁵¹, Hanfei Xu⁵¹, George T O'Connor⁵², Gaurav Thareja⁵³, Omar M E Albagha^{54

55}; Qatar Genome Program Research (QGPR) Consortium; Karsten Suhre^{53

56}, Raquel Granell⁵⁷, Tariq O Faquih⁵⁸, Pieter S Hiemstra⁵⁹, Annelies M Slats⁵⁹, Benjamin H Mullin^{60

61}, Jennie Hui^{62

63

64}, Alan James⁶², John Beilby^{61

62}, Karina Patasova^{65

66}, Pirro Hysi^{65

67}, Jukka T Koskela⁶⁸, Annah B Wyss⁶⁹, Jianping Jin⁷⁰, Sinjini Sikdar^{69

71}, Mikyeong Lee⁶⁹, Sebastian May-Wilson⁷², Nicola Pirastu⁷², Katherine A Kentistou^{72

73}, Peter K Joshi⁷², Paul R H J Timmers⁷², Alexander T Williams², Robert C Free^{4

74}, Xueyang Wang^{4

74}, John L Morrison⁷⁵, Frank D Gilliland⁷⁵, Zhanghua Chen⁷⁵, Carol A Wang^{76

77}, Rachel E Foong^{78

79}, Sarah E Harris⁸⁰, Adele Taylor⁸⁰, Paul Redmond⁸⁰, James P Cook⁸¹, Anubha Mahajan^{82

83}, Lars Lind⁸⁴, Teemu Palviainen⁸⁵, Terho Lehtimäki⁸⁶, Olli T Raitakari^{87

88}, Jaakko Kaprio⁸⁵, Taina Rantanen⁸⁹, Kirsi H Pietiläinen^{90

91}, Simon R Cox⁸⁰, Craig E Pennell^{76

77

92}, Graham L Hall^{78

79}, W James Gauderman⁷⁵, Chris Brightling^{4

93}, James F Wilson^{72

94}, Tuula Vasankari^{95

96}, Tarja Laitinen⁹⁷, Veikko Salomaa⁹⁸, Dennis O Mook-Kanamori^{58

99}, Nicholas J Timpson^{57

100}, Eleftheria Zeggini^{101

102

103}, Josée Dupuis¹⁰⁴, Caroline Hayward¹⁸, Ben Brumpton^{39

105}, Claudia Langenberg^{36

106

107}, Stefan Weiss¹⁰⁸, Georg Homuth¹⁰⁸, Carsten Oliver Schmidt¹⁰⁹, Nicole Probst-Hensch^{21

22}, Marjo-Riitta Jarvelin^{20

110

111

112}, Alanna C Morrison¹⁹, Ozren Polasek¹¹³, Igor Rudan¹¹⁴, Joo-Hyeon Lee^{115

116}, Ian Sayers³, Emma L Rawlins¹¹⁷, Frank Dudbridge², Edwin K Silverman⁵, David P Strachan¹¹⁸, Robin G Walters^{9

10}, Andrew P Morris¹¹⁹, Stephanie J London⁶⁹, Michael H Cho⁵, Louise V Wain^{2

4}, Ian P Hall^#³, Martin D Tobin^#^{120

121}

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Population Health Sciences, University of Leicester, Leicester, UK. nick.shrine@leicester.ac.uk.
² Department of Population Health Sciences, University of Leicester, Leicester, UK.
³ Division of Respiratory Medicine and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.
⁴ Leicester National Institute for Health and Care Research, Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
⁵ Channing Division of Network Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ COPD Foundation, Washington DC, USA.
⁸ Department of Clinical Science, Unversity of Bergen, Bergen, Norway.
⁹ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁰ MRC Population Health Research Unit, University of Oxford, Oxford, UK.
¹¹ Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
¹² Department of Respiratory Diseases, Ghent Universital Hospital, Ghent, Belgium.
¹³ Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
¹⁴ Department of Epidemiology, Eramus Medical Center, Rotterdam, The Netherlands.
¹⁵ Department of Internal Medicine, Eramus Medical Center, Rotterdam, The Netherlands.
¹⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁷ Department of Medicine, Columbia University Medical Center, New York, NY, USA.
¹⁸ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁰ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
²¹ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
²² Department of Public Health, University of Basel, Basel, Switzerland.
²³ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
²⁴ Computational Medicine Core, Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁵ Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany.
²⁶ Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany.
²⁷ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁸ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig Maximilian University, Munich, Germany.
³⁰ Department of Internal Medicine B-Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany.
³¹ Division of Respiratory Medicine, Department of Internal Medicine, Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, USA.
³² Department of Medicine, University of Arizona, Tucson, AZ, USA.
³³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁴ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁵ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁶ MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
³⁷ Department of Public and Primary Care, Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
³⁸ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU Norwegian University of Science and Technology, Trondheim, Norway.
³⁹ HUNT Research Centre, Department of Public Health and Nursing, NTNU Norwegian University of Science and Technology, Levanger, Norway.
⁴⁰ Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
⁴¹ Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴² Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁴³ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁴⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁴⁵ Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁴⁶ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Institute for Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA.
⁵⁰ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵¹ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
⁵² Pulmonary Center, School of Medicine, Boston University, Boston, MA, USA.
⁵³ Bioinformatics Core, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar.
⁵⁴ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁵⁵ Center for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁵⁶ Department of Biophysics and Physiology, Weill Cornell Medicine, New York, NY, USA.
⁵⁷ MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁵⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁹ Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
⁶⁰ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁶¹ School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia.
⁶² Busselton Population Medical Research Institute, QEII Medical Centre, Nedlands, Western Australia, Australia.
⁶³ School of Population and Global Health, University of Western Australia, Crawley, Western Australia, Australia.
⁶⁴ PathWest Laboratory Medicine of WA, Nedlands, Western Australia, Australia.
⁶⁵ Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, UK.
⁶⁶ Division of Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
⁶⁷ UCL Institute of Ophthalmology, University College London, London, UK.
⁶⁸ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁶⁹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
⁷⁰ Westat, Durham, NC, USA.
⁷¹ Department of Mathematics and Statistics, Old Dominion University, Norfolk, VA, USA.
⁷² Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁷³ Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
⁷⁴ Department of Respiratory Sciences, University of Leicester, Leicester, UK.
⁷⁵ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷⁶ School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, New South Wales, Australia.
⁷⁷ Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
⁷⁸ Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, Western Australia, Australia.
⁷⁹ School of Allied Health, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia.
⁸⁰ Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁸¹ Department of Health Data Science, University of Liverpool, Liverpool, UK.
⁸² Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁸³ Genentech, South San Francisco, CA, USA.
⁸⁴ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁸⁵ Institute for Molecular Medicine Finland-FIMM, University of Helsinki, Helsinki, Finland.
⁸⁶ Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁸⁷ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁸⁸ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁸⁹ Faculty of Sport and Health Sciences, University of Jyvaskyla, Jyvaskyla, Finland.
⁹⁰ Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹¹ Obesity and Abdominal Centers, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁹² Department of Maternity and Gynaecology, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁹³ Department of Infection, Inflammation and Immunity, Institute for Lung Health, University of Leicester, Leicester, UK.
⁹⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁹⁵ FILHA-Finnish Lung Health Association, Helsinki, Finland.
⁹⁶ Department of Respiratory Diseases and Allergology, University of Turku, Turku, Finland.
⁹⁷ Administration Center, Tampere University Hospital and University of Tampere, Tampere, Finland.
⁹⁸ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
⁹⁹ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁰ ALSPAC, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁰¹ Wellcome Sanger Institute, Cambridge, UK.
¹⁰² Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁰³ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany.
¹⁰⁴ Department of Epidemiology, Biostatistics, and Occupational Health, School of Population and Global Health, McGill University, Montreal, Quebec, Canada.
¹⁰⁵ Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹⁰⁶ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
¹⁰⁷ Computational Medicine, Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany.
¹⁰⁸ Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁹ Institute for Community Medicine, SHIP-Clinical Epidemiological Research, University Medicine Greifswald, Greifswald, Germany.
¹¹⁰ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹¹¹ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹¹² Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
¹¹³ School of Medicine, University of Split, Split, Croatia.
¹¹⁴ Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
¹¹⁵ Jeffrey Cheah Biomedical Centre, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
¹¹⁶ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
¹¹⁷ Wellcome Trust-CRUK Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
¹¹⁸ Population Health Research Institute, St George's University of London, London, UK.
¹¹⁹ Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
¹²⁰ Department of Population Health Sciences, University of Leicester, Leicester, UK. martin.tobin@leicester.ac.uk.
¹²¹ Leicester National Institute for Health and Care Research, Biomedical Research Centre, Glenfield Hospital, Leicester, UK. martin.tobin@leicester.ac.uk.

^# Contributed equally.

PMID: 36914875
PMCID: PMC10011137
DOI: 10.1038/s41588-023-01314-0

Meta-Analysis

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Nick Shrine et al. Nat Genet. 2023 Mar.

. 2023 Mar;55(3):410-422.

doi: 10.1038/s41588-023-01314-0. Epub 2023 Mar 13.

Authors

Collaborators

Affiliations

¹ Department of Population Health Sciences, University of Leicester, Leicester, UK. nick.shrine@leicester.ac.uk.
² Department of Population Health Sciences, University of Leicester, Leicester, UK.
³ Division of Respiratory Medicine and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.
⁴ Leicester National Institute for Health and Care Research, Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
⁵ Channing Division of Network Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ COPD Foundation, Washington DC, USA.
⁸ Department of Clinical Science, Unversity of Bergen, Bergen, Norway.
⁹ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁰ MRC Population Health Research Unit, University of Oxford, Oxford, UK.
¹¹ Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
¹² Department of Respiratory Diseases, Ghent Universital Hospital, Ghent, Belgium.
¹³ Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
¹⁴ Department of Epidemiology, Eramus Medical Center, Rotterdam, The Netherlands.
¹⁵ Department of Internal Medicine, Eramus Medical Center, Rotterdam, The Netherlands.
¹⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁷ Department of Medicine, Columbia University Medical Center, New York, NY, USA.
¹⁸ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁰ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
²¹ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
²² Department of Public Health, University of Basel, Basel, Switzerland.
²³ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
²⁴ Computational Medicine Core, Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁵ Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany.
²⁶ Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany.
²⁷ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁸ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig Maximilian University, Munich, Germany.
³⁰ Department of Internal Medicine B-Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany.
³¹ Division of Respiratory Medicine, Department of Internal Medicine, Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, USA.
³² Department of Medicine, University of Arizona, Tucson, AZ, USA.
³³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁴ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁵ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁶ MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
³⁷ Department of Public and Primary Care, Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
³⁸ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU Norwegian University of Science and Technology, Trondheim, Norway.
³⁹ HUNT Research Centre, Department of Public Health and Nursing, NTNU Norwegian University of Science and Technology, Levanger, Norway.
⁴⁰ Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
⁴¹ Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴² Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁴³ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁴⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁴⁵ Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁴⁶ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Institute for Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA.
⁵⁰ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵¹ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
⁵² Pulmonary Center, School of Medicine, Boston University, Boston, MA, USA.
⁵³ Bioinformatics Core, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar.
⁵⁴ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁵⁵ Center for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁵⁶ Department of Biophysics and Physiology, Weill Cornell Medicine, New York, NY, USA.
⁵⁷ MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁵⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁹ Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
⁶⁰ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁶¹ School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia.
⁶² Busselton Population Medical Research Institute, QEII Medical Centre, Nedlands, Western Australia, Australia.
⁶³ School of Population and Global Health, University of Western Australia, Crawley, Western Australia, Australia.
⁶⁴ PathWest Laboratory Medicine of WA, Nedlands, Western Australia, Australia.
⁶⁵ Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, UK.
⁶⁶ Division of Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
⁶⁷ UCL Institute of Ophthalmology, University College London, London, UK.
⁶⁸ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁶⁹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
⁷⁰ Westat, Durham, NC, USA.
⁷¹ Department of Mathematics and Statistics, Old Dominion University, Norfolk, VA, USA.
⁷² Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁷³ Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
⁷⁴ Department of Respiratory Sciences, University of Leicester, Leicester, UK.
⁷⁵ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷⁶ School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, New South Wales, Australia.
⁷⁷ Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
⁷⁸ Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, Western Australia, Australia.
⁷⁹ School of Allied Health, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia.
⁸⁰ Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁸¹ Department of Health Data Science, University of Liverpool, Liverpool, UK.
⁸² Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁸³ Genentech, South San Francisco, CA, USA.
⁸⁴ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁸⁵ Institute for Molecular Medicine Finland-FIMM, University of Helsinki, Helsinki, Finland.
⁸⁶ Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁸⁷ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁸⁸ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁸⁹ Faculty of Sport and Health Sciences, University of Jyvaskyla, Jyvaskyla, Finland.
⁹⁰ Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹¹ Obesity and Abdominal Centers, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁹² Department of Maternity and Gynaecology, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁹³ Department of Infection, Inflammation and Immunity, Institute for Lung Health, University of Leicester, Leicester, UK.
⁹⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁹⁵ FILHA-Finnish Lung Health Association, Helsinki, Finland.
⁹⁶ Department of Respiratory Diseases and Allergology, University of Turku, Turku, Finland.
⁹⁷ Administration Center, Tampere University Hospital and University of Tampere, Tampere, Finland.
⁹⁸ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
⁹⁹ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁰ ALSPAC, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁰¹ Wellcome Sanger Institute, Cambridge, UK.
¹⁰² Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁰³ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany.
¹⁰⁴ Department of Epidemiology, Biostatistics, and Occupational Health, School of Population and Global Health, McGill University, Montreal, Quebec, Canada.
¹⁰⁵ Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹⁰⁶ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
¹⁰⁷ Computational Medicine, Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany.
¹⁰⁸ Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁹ Institute for Community Medicine, SHIP-Clinical Epidemiological Research, University Medicine Greifswald, Greifswald, Germany.
¹¹⁰ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹¹¹ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹¹² Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
¹¹³ School of Medicine, University of Split, Split, Croatia.
¹¹⁴ Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
¹¹⁵ Jeffrey Cheah Biomedical Centre, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
¹¹⁶ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
¹¹⁷ Wellcome Trust-CRUK Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
¹¹⁸ Population Health Research Institute, St George's University of London, London, UK.
¹¹⁹ Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
¹²⁰ Department of Population Health Sciences, University of Leicester, Leicester, UK. martin.tobin@leicester.ac.uk.
¹²¹ Leicester National Institute for Health and Care Research, Biomedical Research Centre, Glenfield Hospital, Leicester, UK. martin.tobin@leicester.ac.uk.

^# Contributed equally.

PMID: 36914875
PMCID: PMC10011137
DOI: 10.1038/s41588-023-01314-0

Erratum in

Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.
Shrine N, Izquierdo AG, Chen J, Packer R, Hall RJ, Guyatt AL, Batini C, Thompson RJ, Pavuluri C, Malik V, Hobbs BD, Moll M, Kim W, Tal-Singer R, Bakke P, Fawcett KA, John C, Coley K, Piga NN, Pozarickij A, Lin K, Millwood IY, Chen Z, Li L; China Kadoorie Biobank Collaborative Group; Wijnant SRA, Lahousse L, Brusselle G, Uitterlinden AG, Manichaikul A, Oelsner EC, Rich SS, Barr RG, Kerr SM, Vitart V, Brown MR, Wielscher M, Imboden M, Jeong A, Bartz TM, Gharib SA, Flexeder C, Karrasch S, Gieger C, Peters A, Stubbe B, Hu X, Ortega VE, Meyers DA, Bleecker ER, Gabriel SB, Gupta N, Smith AV, Luan J, Zhao JH, Hansen AF, Langhammer A, Willer C, Bhatta L, Porteous D, Smith BH, Campbell A, Sofer T, Lee J, Daviglus ML, Yu B, Lim E, Xu H, O'Connor GT, Thareja G, Albagha OME; Qatar Genome Program Research (QGPR) Consortium; Suhre K, Granell R, Faquih TO, Hiemstra PS, Slats AM, Mullin BH, Hui J, James A, Beilby J, Patasova K, Hysi P, Koskela JT, Wyss AB, Jin J, Sikdar S, Lee M, May-Wilson S, Pirastu N, Kentistou KA, Joshi PK, Timmers PRHJ, Williams AT, Free RC, Wang X, Morrison JL, Gilliland FD, Chen Z, Wang CA, Foong RE, Harris SE, Taylor A, Redmond P, Cook JP, Mahajan A, Lind L, Palviainen T,… See abstract for full author list ➔ Shrine N, et al. Nat Genet. 2023 Oct;55(10):1778-1779. doi: 10.1038/s41588-023-01531-7. Nat Genet. 2023. PMID: 37749248 Free PMC article. No abstract available.

Abstract

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

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Conflict of interest statement

M.D.T. and L.V.W. have previously received funding from GSK for collaborative research projects outside of the submitted work. I.P.H. has funded research collaborations with GSK, Boehringer Ingelheim and Orion. M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. B.D.H. has received grant funding from Bayer and speaking or consulting fees from AstraZeneca. I.S. has funded research collaborations with GSK, Boehringer Ingelheim and Orion outside of the submitted work. R.J.P., M.D.T., C.J. and L.V.W. have a funded research collaboration with Orion for collaborative research projects outside of the submitted work. The other authors declare no competing interests.

Figures

**Fig. 1. Study overview.**
a, Discovery meta-analysis. *For signals present in more than one trait, the signal is only counted once (for the most significant trait). b, Pathway analyses, GRS analyses and PheWAS studies.

**Fig. 2. 135 genes prioritized with ≥3 variant-to-gene criteria.**
The number of variant-to-gene criteria implicating the gene is in brackets after the gene name. The gray in the first eight columns indicates that at least one variant implicates the gene as causal via the evidence for that column. The last four columns indicate the level of association of the most significant variant implicating the gene as causal with respect to the FEV₁/FVC decreasing allele; red indicates that this association is in the same direction of effect as the FEV₁/FVC decreasing allele and blue indicates the opposite direction with the shade indicating P < the corresponding value in the legend.

**Fig. 3. GRS performance.**
a, Prediction performance of three GRSs across ancestry groups for FEV₁/FVC shown as the s.d. change in FEV₁/FVC per s.d. increase in GRS for individuals in the UK Biobank grouped according to ancestry. Sample sizes: AFR, n = 4,227; AMR, n = 2,798; EAS, n = 1,564; and EUR, n = 320,656. b, Prediction performance of three GRSs for COPD shown as COPD odds ratio per s.d. increase in GRS. Sample sizes: AFR, 250 cases and 3,977 controls; AMR, n = 151 cases and 2,647 controls; EUR, 24,062 cases and 296,594 controls. UKB, UK Biobank. c, Odds ratio for COPD per s.d. change in GRS in COPD case–control studies. P values were calculated from a logistic regression adjusted for age, age squared, sex, height and principal components, followed by fixed-effect meta-analysis. d, Decile analysis meta-analyzed across five EUR studies shown as the COPD odds ratio compared between members of each decile and the reference decile. n = 11,074 (4,328 cases and 6,746 controls). Statistical tests were two-sided, the height of the bars show the point estimate of the effect and whiskers show the 95% CI. OR, odds ratio.

**Fig. 4. PheWAS for FEV₁/FVC-weighted GRS partitioned according to elastic fiber formation.**
Reactome pathway database. CP, composite phenotype and DFP, Data-Field ID phenotype (Methods). The peach-colored line means FDR 1%.

**Fig. 5. PheWAS for FEV₁/FVC-weighted GRS partitioned according to the PI3K–Akt signaling pathway in *Homo sapiens*.**
Kyoto Encyclopedia of Genes and Genomes. CP, composite phenotype; DFP, Data-Field ID phenotype (Methods). The peach-colored line means FDR 1%.

**Fig. 6. PheWAS for FEV₁/FVC-weighted GRS partitioned according to hypertrophic cardiomyopathy in *H. sapiens*.**
Kyoto Encyclopedia of Genes and Genomes. CP, composite phenotype; DFP, Data-Field ID phenotype (Methods). The peach-colored line means FDR 1%.

**Fig. 7. PheWAS for FEV₁/FVC-weighted GRS partitioned according to signal transduction.**
Reactome pathway database. CP, composite phenotype (Methods). The peach-colored line means FDR 1%.

See this image and copyright information in PMC

Comment in

Genetic insights into lung function inform better management of respiratory diseases.
Qin N, Wang C, Hu Z. Qin N, et al. Cell Rep Med. 2023 May 16;4(5):101041. doi: 10.1016/j.xcrm.2023.101041. Cell Rep Med. 2023. PMID: 37196630 Free PMC article.

References

1. Young RP, Hopkins R, Eaton TE. Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes. Eur. Respir. J. 2007;30:616–622. - PubMed
1. GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir. Med. 2020;8:585–596. - PMC - PubMed
1. Sirugo G, Williams SM, Tishkoff SA. The missing diversity in human genetic studies. Cell. 2019;177:26–31. - PMC - PubMed
1. Tobin MD, Izquierdo AG. Improving ethnic diversity in respiratory genomics research. Eur. Respir. J. 2021;58:2101615. - PubMed
1. Shrine N, et al. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nat. Genet. 2019;51:481–493. - PMC - PubMed

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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

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