New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries
New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries
Abstract Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
Whittaker John C、Nickle David C、Meyers Deborah A、Stubbe Beate、Packer Richard、Parker Margaret M、Paynton Megan L、Prokopenko Dmitry、Sayers Ian、Sin Don D、Sparrow David、Van den Berge Maarten、Raitakari Olli T、Gyllensten Ulf、Deary Ian J、Probst-Hensch Nicole M、James Alan L、Wilson James F、Hayward Caroline、Hall Ian P、Tobin Martin D、Wain Louise V、Shrine Nick、Fawcett Katherine A、Reeve Nicola F、Zhao Jing Hua、Wielscher Matthias、Weiss Stefan、Cook James P、Hui Jennie、Karrasch Stefan、Harris Sarah E、Marten Jonathan、Allen Richard J、Chen Zhengming、Ewert Ralf、Hansell Anna L、Hao Ke、Hoffman Josh D、Li Liming、Locantore Nick、Artigas Mar¨aa Soler、Li Xingnan、Wareham Nick、Bleecker Eugene R、Joshi Peter K、Beaty Terri H、Zhou Jian、Rudan Igor、Erzurumluoglu A Mesut、Gieger Christian、DeMeo Dawn L、M Yerges Armstrong Laura、Melbourne Carl、Schulz Holger、Lehtim?ki Terho、Maranville Joseph C、Crapo James D、Dudbridge Frank、Boxall Ruth、Lind Lars、Morris Andrew P、Timmers Paul RHJ、Surakka Ida、Kerr Shona M、Scott Robert A、Rawal Rajesh、Joubert Philippe、Obeidat Ma?ˉen、Jarvelin Marjo-Riitta、Hobbs Brian D、Enroth Stefan、Zeggini Eleftheria、Runz Heiko、Sun Benjamin B、Bakke Per S、Murray Alison、Silverman Edwin K、Walters Robin G、Hokanson John、Porteous David、Luan Jian?ˉan、K?h?nen Mika、Guyatt Anna L、Kentistou Katherine A、Polasek Ozren、Butterworth Adam S、H Smith Blair、Danesh John、Boss¨| Yohan、Brandsma Corry-Anke、Society Scientific Group Understanding、Batini Chiara、Langenberg Claudia、Strachan David P、Jackson Victoria E、Gulsvik Amund、Li Xuan、Lin Kuang、Homuth Georg、Cho Michael H、Mahajan Anubha、Tal-Singer Ruth、Troyanskaya Olga G、Qiao Dandi、Imboden Medea、Vitart Veronique、Sakornsakolpat Phuwanat、Song Kijoung、Woodruff Prescott
Target Sciences - R&D, GSK Medicines Research Centre, Gunnels Wood RoadMerck Research Laboratories, Genetics and Pharmacogenomics,Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of ArizonaDepartment of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine GreifswaldDepartment of Health Sciences, University of LeicesterChanning Division of Network Medicine, Brigham and Women ?ˉ s HospitaDepartment of Health Sciences, University of LeicesterChanning Division of Network Medicine, Brigham and Women ?ˉ s HospitaDivision of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of NottinghamThe University of British Columbia Centre for Heart Lung Innovation||Respiratory Division, Department of Medicine, University of British ColumbiaVA Boston Healthcare System||Department of Medicine, Boston University School of MedicineUniversity of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of GroningenDepartment of Clinical Physiology and Nuclear Medicine, Turku University Hospital||Research Centre of Applied and Preventive Cardiovascular Medicine, University of TurkuDepartment of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life LaboratoryCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh||Department of Psychology, University of EdinburghSwiss Tropical and Public Health Institute||University of BaselBusselton Population Medical Research Institute, Sir Charles Gairdner Hospital||Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital||School of Medicine and Pharmacology, The University of Western AustraliaCentre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh||Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh,Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh,Division of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of NottinghamDepartment of Health Sciences, University of Leicester||National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield HospitalDepartment of Health Sciences, University of Leicester||National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield HospitalDepartment of Health Sciences, University of LeicesterDepartment of Health Sciences, University of LeicesterDepartment of Health Sciences, University of LeicesterMRC Epidemiology Unit, University of Cambridge School of Clinical MedicineDepartment of Epidemiology and Biostatistics, MRC ¨C PHE Centre for Environment & Health, School of Public Health, Imperial College LondonInterfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine GreifswaldDepartment of Biostatistics, University of LiverpoolBusselton Population Medical Research Institute, Sir Charles Gairdner Hospital||School of Population Health, The University of Western Australia||PathWest Laboratory Medicine of WA, Sir Charles Gairdner Hospital||School of Pathology and Laboratory Medicine, The University of Western AustraliaInstitute of Epidemiology, Helmholtz Zentrum Muenchen ¨C German Research Center for Environmental Health||Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universit?t||Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh||Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General HospitalMedical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh,Department of Health Sciences, University of LeicesterNuffield Department of Population Health, University of OxfordDepartment of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine GreifswaldUK Small Area Health Statistics Unit, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London||Imperial College Healthcare NHS Trust, St Mary ?ˉ s Hospital, PaddingtonIcahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount SinaiTarget Sciences, GlaxoSmithKlineDepartment of Epidemiology & Biostatistics, Peking University Health Science Centre, Peking UniversityGSK R&D, CollegevillePsychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Aut¨?noma de Barcelona||Department of Psychiatry, Hospital Universitari Vall d'Hebron||Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos IIIDivision of Genetics, Genomics and Precision Medicine, Department of Medicine, University of ArizonaMRC Epidemiology Unit, University of Cambridge School of Clinical MedicineDivision of Genetics, Genomics and Precision Medicine, Department of Medicine, University of ArizonaCentre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of EdinburghDepartment of Epidemiology, Johns Hopkins University School of Public HealthFlatiron Institute, Simons Foundation, New YorkCentre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of EdinburghDepartment of Health Sciences, University of LeicesterDepartment of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen ¨C German Research Center for Environmental HealthChanning Division of Network Medicine, Brigham and Women ?ˉ s HospitaTarget Sciences, GlaxoSmithKlineDepartment of Health Sciences, University of LeicesterInstitute of Epidemiology, Helmholtz Zentrum Muenchen ¨C German Research Center for Environmental Health||Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of TampereMRL, Merck & Co., Inc., KenilworthNational Jewish Health||Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish HealthDepartment of Health Sciences, University of LeicesterNuffield Department of Population Health, University of Oxford||Medical Research Council Population Health Research Unit, University of OxfordDepartment of Medical Sciences, Cardiovascular Epidemiology, Uppsala UniversityDepartment of Biostatistics, University of Liverpool||Wellcome Trust Centre for Human Genetics, University of OxfordCentre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of EdinburghInstitute for Molecular Medicine Finland (FIMM), University of Helsinki||The National Institute for Health and Welfare (THL)Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh,Target Sciences - R&D, GSK Medicines Research Centre, Gunnels Wood RoadDepartment of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen ¨C German Research Center for Environmental HealthInstitut Universitaire de Cardiologie et de Pneumologie de Qu¨|bec, Laval University||Department of Molecular Biology, Medical Biochemistry, and Pathology, Laval UniversityThe University of British Columbia Centre for Heart Lung InnovationDepartment of Epidemiology and Biostatistics, MRC ¨C PHE Centre for Environment & Health, School of Public Health, Imperial College London||Center for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter Oulu, University of Oulu||Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20Channing Division of Network Medicine, Brigham and Women ?ˉ s Hospita||Division of Pulmonary and Critical Care Medicine, Brigham and Women ?ˉ s HospitalDepartment of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life LaboratoryWellcome Trust Sanger InstituteMRL, Merck & Co., Inc., KenilworthMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of CambridgeDepartment of Clinical Science, University of BergenThe Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of AberdeenChanning Division of Network Medicine, Brigham and Women ?ˉ s Hospita||Division of Pulmonary and Critical Care Medicine, Brigham and Women ?ˉ s HospitalNuffield Department of Population Health, University of OxfordDepartment of Epidemiology, University of Colorado Anschutz Medical CampusCentre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital||Centre for Cognitive Ageing and Cognitive Epidemiology, University of EdinburghMRC Epidemiology Unit, University of Cambridge School of Clinical MedicineDepartment of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of TampereDepartment of Health Sciences, University of LeicesterCentre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh||Centre for Cardiovascular Sciences, Queen ?ˉ s Medical Research Institute, University of EdinburghUniversity of Split School of Medicine||Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of EdinburghMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of CambridgeDivision of Population Health Sciences, Ninewells Hospital and Medical School, University of DundeeMRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke ?ˉ s Hospital||Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton||NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of CambridgeDepartment of Molecular Medicine, Laval University||Institut Universitaire de Cardiologie et de Pneumologie de Qu¨|bec, Laval UniversityUniversity of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, University of GroningenA list of contributors can be found in the Supplementary AppendixDepartment of Health Sciences, University of LeicesterMRC Epidemiology Unit, University of Cambridge School of Clinical MedicinePopulation Health Research Institute, St George ?ˉ s, University of LondonDepartment of Health Sciences, University of Leicester||Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research||Department of Medical Biology, University of Melbourne,Department of Clinical Science, University of BergenThe University of British Columbia Centre for Heart Lung InnovationNuffield Department of Population Health, University of OxfordInterfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine GreifswaldChanning Division of Network Medicine, Brigham and Women ?ˉ s Hospita||Division of Pulmonary and Critical Care Medicine, Brigham and Women ?ˉ s HospitalWellcome Trust Centre for Human Genetics, University of OxfordGSK R&D, CollegevilleDepartment of Computer Science, Princeton University, Princeton||Lewis-Sigler Institute for Integrative Genomics, Princeton UniversityChanning Division of Network Medicine, Brigham and Women ?ˉ s HospitaSwiss Tropical and Public Health Institute||University of BaselMedical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh,Channing Division of Network Medicine, Brigham and Women ?ˉ s Hospita||Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol UniversityTarget Sciences, GlaxoSmithKlineUCSF Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco
医药卫生理论医学研究方法基础医学
Whittaker John C,Nickle David C,Meyers Deborah A,Stubbe Beate,Packer Richard,Parker Margaret M,Paynton Megan L,Prokopenko Dmitry,Sayers Ian,Sin Don D,Sparrow David,Van den Berge Maarten,Raitakari Olli T,Gyllensten Ulf,Deary Ian J,Probst-Hensch Nicole M,James Alan L,Wilson James F,Hayward Caroline,Hall Ian P,Tobin Martin D,Wain Louise V,Shrine Nick,Fawcett Katherine A,Reeve Nicola F,Zhao Jing Hua,Wielscher Matthias,Weiss Stefan,Cook James P,Hui Jennie,Karrasch Stefan,Harris Sarah E,Marten Jonathan,Allen Richard J,Chen Zhengming,Ewert Ralf,Hansell Anna L,Hao Ke,Hoffman Josh D,Li Liming,Locantore Nick,Artigas Mar¨aa Soler,Li Xingnan,Wareham Nick,Bleecker Eugene R,Joshi Peter K,Beaty Terri H,Zhou Jian,Rudan Igor,Erzurumluoglu A Mesut,Gieger Christian,DeMeo Dawn L,M Yerges Armstrong Laura,Melbourne Carl,Schulz Holger,Lehtim?ki Terho,Maranville Joseph C,Crapo James D,Dudbridge Frank,Boxall Ruth,Lind Lars,Morris Andrew P,Timmers Paul RHJ,Surakka Ida,Kerr Shona M,Scott Robert A,Rawal Rajesh,Joubert Philippe,Obeidat Ma?ˉen,Jarvelin Marjo-Riitta,Hobbs Brian D,Enroth Stefan,Zeggini Eleftheria,Runz Heiko,Sun Benjamin B,Bakke Per S,Murray Alison,Silverman Edwin K,Walters Robin G,Hokanson John,Porteous David,Luan Jian?ˉan,K?h?nen Mika,Guyatt Anna L,Kentistou Katherine A,Polasek Ozren,Butterworth Adam S,H Smith Blair,Danesh John,Boss¨| Yohan,Brandsma Corry-Anke,Society Scientific Group Understanding,Batini Chiara,Langenberg Claudia,Strachan David P,Jackson Victoria E,Gulsvik Amund,Li Xuan,Lin Kuang,Homuth Georg,Cho Michael H,Mahajan Anubha,Tal-Singer Ruth,Troyanskaya Olga G,Qiao Dandi,Imboden Medea,Vitart Veronique,Sakornsakolpat Phuwanat,Song Kijoung,Woodruff Prescott.New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries[EB/OL].(2025-03-28)[2025-06-22].https://www.biorxiv.org/content/10.1101/343293.点此复制
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