Wellcome Open Research (Aug 2018)
Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 3; referees: 2 approved]
- Victoria E. Jackson,
- Jeanne C. Latourelle,
- Louise V. Wain,
- Albert V. Smith,
- Megan L. Grove,
- Traci M. Bartz,
- Ma'en Obeidat,
- Michael A. Province,
- Wei Gao,
- Beenish Qaiser,
- David J. Porteous,
- Patricia A. Cassano,
- Tarunveer S. Ahluwalia,
- Niels Grarup,
- Jin Li,
- Elisabeth Altmaier,
- Jonathan Marten,
- Sarah E. Harris,
- Ani Manichaikul,
- Tess D. Pottinger,
- Ruifang Li-Gao,
- Allan Lind-Thomsen,
- Anubha Mahajan,
- Lies Lahousse,
- Medea Imboden,
- Alexander Teumer,
- Bram Prins,
- Leo-Pekka Lyytikäinen,
- Gudny Eiriksdottir,
- Nora Franceschini,
- Colleen M. Sitlani,
- Jennifer A. Brody,
- Yohan Bossé,
- Wim Timens,
- Aldi Kraja,
- Anu Loukola,
- Wenbo Tang,
- Yongmei Liu,
- Jette Bork-Jensen,
- Johanne M. Justesen,
- Allan Linneberg,
- Leslie A. Lange,
- Rajesh Rawal,
- Stefan Karrasch,
- Jennifer E. Huffman,
- Blair H. Smith,
- Gail Davies,
- Kristin M. Burkart,
- Josyf C. Mychaleckyj,
- Tobias N. Bonten,
- Stefan Enroth,
- Lars Lind,
- Guy G. Brusselle,
- Ashish Kumar,
- Beate Stubbe,
- Understanding Society Scientific Group,
- Mika Kähönen,
- Annah B. Wyss,
- Bruce M. Psaty,
- Susan R. Heckbert,
- Ke Hao,
- Taina Rantanen,
- Stephen B. Kritchevsky,
- Kurt Lohman,
- Tea Skaaby,
- Charlotta Pisinger,
- Torben Hansen,
- Holger Schulz,
- Ozren Polasek,
- Archie Campbell,
- John M. Starr,
- Stephen S. Rich,
- Dennis O. Mook-Kanamori,
- Åsa Johansson,
- Erik Ingelsson,
- André G. Uitterlinden,
- Stefan Weiss,
- Olli T. Raitakari,
- Vilmundur Gudnason,
- Kari E. North,
- Sina A. Gharib,
- Don D. Sin,
- Kent D. Taylor,
- George T. O'Connor,
- Jaakko Kaprio,
- Tamara B. Harris,
- Oluf Pederson,
- Henrik Vestergaard,
- James G. Wilson,
- Konstantin Strauch,
- Caroline Hayward,
- Shona Kerr,
- Ian J. Deary,
- R. Graham Barr,
- Renée de Mutsert,
- Ulf Gyllensten,
- Andrew P. Morris,
- M. Arfan Ikram,
- Nicole Probst-Hensch,
- Sven Gläser,
- Eleftheria Zeggini,
- Terho Lehtimäki,
- David P. Strachan,
- Josée Dupuis,
- Alanna C. Morrison,
- Ian P. Hall,
- Martin D. Tobin,
- Stephanie J. London
Affiliations
- Victoria E. Jackson
- Department of Health Sciences, University of Leicester, Leicester, UK
- Jeanne C. Latourelle
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
- Louise V. Wain
- Department of Health Sciences, University of Leicester, Leicester, UK
- Albert V. Smith
- Icelandic Heart Association, 201 Kopavogur, Iceland
- Megan L. Grove
- 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, 77030, USA
- Traci M. Bartz
- Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, 98101, USA
- Ma'en Obeidat
- The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada
- Michael A. Province
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
- Wei Gao
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
- Beenish Qaiser
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Helsinki, Finland
- David J. Porteous
- Centre for Genomic & Experimental Medicine, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Patricia A. Cassano
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
- Tarunveer S. Ahluwalia
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Jin Li
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
- Elisabeth Altmaier
- Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Jonathan Marten
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh , EH4 2XU, UK
- Sarah E. Harris
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Ani Manichaikul
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Tess D. Pottinger
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
- Allan Lind-Thomsen
- Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden
- Anubha Mahajan
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Lies Lahousse
- Respiratory Medicine, Ghent University Hospital, Ghent, BE9000, Belgium
- Medea Imboden
- Swiss Tropical and Public Health Institute, Basel, Switzerland
- Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
- Bram Prins
- Human Genetics, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK
- Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland
- Gudny Eiriksdottir
- University of Iceland, 101 Reykjavik, Iceland
- Nora Franceschini
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27514, USA
- Colleen M. Sitlani
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA
- Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA
- Yohan Bossé
- Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada
- Wim Timens
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, NL9713 GZ, Netherlands
- Aldi Kraja
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
- Anu Loukola
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Helsinki, Finland
- Wenbo Tang
- Boehringer Ingelheim , Danbury, CT, USA
- Yongmei Liu
- Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
- Jette Bork-Jensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Johanne M. Justesen
- Steno Diabetes Center Copenhagen, Gentofte, 2820, Denmark
- Allan Linneberg
- Centre for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
- Leslie A. Lange
- Department of Medicine, Division of Bioinformatics and Personalized Medicine, University of Colorado Denver, Aurora, CO, USA
- Rajesh Rawal
- Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Stefan Karrasch
- Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Jennifer E. Huffman
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh , EH4 2XU, UK
- Blair H. Smith
- Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
- Gail Davies
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Kristin M. Burkart
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Josyf C. Mychaleckyj
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Tobias N. Bonten
- Department of Pulmonology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
- Stefan Enroth
- Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden
- Lars Lind
- Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
- Guy G. Brusselle
- Epidemiology, Erasmus Medical Center, Rotterdam, 3000CA, Netherlands
- Ashish Kumar
- University of Basel, Basel, Switzerland
- Beate Stubbe
- Internal Medicine B, University Medicine Greifswald, Greifswald, 17475, Germany
- Understanding Society Scientific Group
- Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland
- Annah B. Wyss
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, 27709, USA
- Bruce M. Psaty
- Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, 98101, USA
- Susan R. Heckbert
- Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA
- Ke Hao
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA
- Taina Rantanen
- Department of Health Sciences, University of Jyväskylä, Jyväskylä, Fl-40014, Finland
- Stephen B. Kritchevsky
- Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Kurt Lohman
- Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
- Tea Skaaby
- Centre for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
- Charlotta Pisinger
- Centre for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
- Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Holger Schulz
- Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Ozren Polasek
- Faculty of Medicine, University of Split, Split, Croatia
- Archie Campbell
- Centre for Genomic & Experimental Medicine, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- John M. Starr
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Dennis O. Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
- Åsa Johansson
- Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden
- Erik Ingelsson
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- André G. Uitterlinden
- Internal Medicine, Erasmus Medical Center, Rotterdam, 3000CA, Netherlands
- Stefan Weiss
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany
- Olli T. Raitakari
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland
- Vilmundur Gudnason
- Icelandic Heart Association, 201 Kopavogur, Iceland
- Kari E. North
- Department of Epidemiology and Carolina Center for Genome Science, University of North Carolina, Chapel Hill, NC, 27514, USA
- Sina A. Gharib
- Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, WA, 98109, USA
- Don D. Sin
- The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada
- Kent D. Taylor
- Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
- George T. O'Connor
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
- Jaakko Kaprio
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Helsinki, Finland
- Tamara B. Harris
- National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
- Oluf Pederson
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Henrik Vestergaard
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- James G. Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany
- Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh , EH4 2XU, UK
- Shona Kerr
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh , EH4 2XU, UK
- Ian J. Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- R. Graham Barr
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Renée de Mutsert
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
- Ulf Gyllensten
- Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden
- Andrew P. Morris
- Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK
- M. Arfan Ikram
- Epidemiology, Erasmus Medical Center, Rotterdam, 3000CA, Netherlands
- Nicole Probst-Hensch
- Swiss Tropical and Public Health Institute, Basel, Switzerland
- Sven Gläser
- Internal Medicine B, University Medicine Greifswald, Greifswald, 17475, Germany
- Eleftheria Zeggini
- Human Genetics, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK
- Terho Lehtimäki
- Department of Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland
- David P. Strachan
- Population Health Research Institute, St George's, University of London, London, SW17 0RE, UK
- Josée Dupuis
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
- Alanna C. Morrison
- 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, 77030, USA
- Ian P. Hall
- NIHR Nottingham Biomedical Research Centre and Division of Respiratory Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
- Martin D. Tobin
- Department of Health Sciences, University of Leicester, Leicester, UK
- Stephanie J. London
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, 27709, USA
- DOI
- https://doi.org/10.12688/wellcomeopenres.12583.3
- Journal volume & issue
-
Vol. 3
Abstract
Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Keywords
