Journal article

Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

Maria Soler Artigas, Louise V Wain, Suzanne Miller, Abdul Kader Kheirallah, Jennifer E Huffman, Ioanna Ntalla, Nick Shrine, Ma'en Obeidat, Holly Trochet, Wendy L McArdle, Alexessander Couto Alves, Jennie Hui, Jing Hua Zhao, Peter K Joshi, Alexander Teumer, Eva Albrecht, Medea Imboden, Rajesh Rawal, Lorna M Lopez, Jonathan Marten Show all

Nature Communications | Nature Research (part of Springer Nature) | Published : 2015

Abstract

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

University of Melbourne Researchers

Grants

Awarded by Medical Research Council Senior Clinical Fellowship


Awarded by Medical Research Council programme


Awarded by Medical Research Council


Awarded by Wellcome Trust


Awarded by Wellcome Trust Strategic Award


Awarded by European Commission


Awarded by Ministry of Science, Education and Sport in the Republic of Croatia


Awarded by Croatian Science Foundation


Awarded by European Union


Awarded by Chief Scientist Office


Awarded by Academy of Finland


Awarded by Center of Excellence in Complex Disease Genetics, EU


Awarded by German Federal Ministry of Education and Research


Awarded by subnetwork COSYCONET


Awarded by UK's Biotechnology and Biological Sciences Research Council (BBSRC)


Awarded by University of Oulu, Finland


Awarded by NHLBI through the STAMPEED program


Awarded by NIH/NIMH


Awarded by EU


Awarded by Medical Research Council, UK


Awarded by Swedish Medical Research Council


Awarded by Swiss National Science Foundation


Awarded by COPD Network (COSYCONET)


Awarded by Federal State of Mecklenburg-West Pomerania


Awarded by Tampere University Hospital Medical Funds


Awarded by Medical Research Council (MRC)


Awarded by MRC fellowships


Awarded by MRC programme


Awarded by ERC Consolidator Grant


Awarded by EU (GABRIEL)


Awarded by ECRHS II


Awarded by US National Institutes of Health/National Eye Institute


Awarded by Swedish Foundation for Strategic Research


Awarded by Swedish Research Council


Awarded by Swedish Heart-Lung Foundation


Awarded by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX)



Funding Acknowledgements

The research undertaken by M.D.T., M.S.A. and L.V.W. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). This research used the ALICE High Performance Computing Facility at the University of Leicester. The Universities of Leicester and Nottingham acknowledge receipt of a Collaborative Research and Development grant from the Healthcare and Bioscience iNet, a project funded by the East Midlands Development Agency, part-financed by the European Regional Development Fund and delivered by Medilink East Midlands. I.P.H. holds a Medical Research Council programme grant (G1000861). We acknowledge the use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The B58C-GABRIEL genotyping was supported by a contract from the European Commission Framework Programme 6 (018996) and grants from the French Ministry of Research. The Busselton Health Study (BHS) acknowledges the generous support for the 1994/5 follow-up study from Healthway, Western Australia and the numerous Busselton community volunteers who assisted with data collection and the study participants from the Shire of Busselton. The BHS is supported by The Great Wine Estates of the Margaret River region of Western Australia. GWAS genotyping was supported by a research collaboration with Pfizer. The CROATIA study was supported through grants from the Medical Research Council UK, the Ministry of Science, Education and Sport in the Republic of Croatia (number 216-1080315-0302), Croatian Science Foundation (grant number 8875) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). SNP genotyping for CROATIA-Vis was performed by the Wellcome Trust Clinical Research Facility (WTCRF) at the Western General Hospital, Edinburgh, UK. CROATIA-Korcula was genotyped by Helmholz Zentrum Munchen, GmbH, Neuherberg, Germany and CROATIA-Split by AROS Applied Biotechnology, Aarhus, Denmark. We would like to acknowledge the invaluable contributions of the recruitment teams in Croatia (including those from the Institute of Anthropological Research in Zagreb and the Croatian Centre for Global Health at the University of Split), the administrative teams in Croatia and Edinburgh and the people of Korcula, Vis and Split.r The EPIC Norfolk Study is funded by program grants from the Medical Research Council UK and Cancer Research UK, and by additional support from the European Union, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency and the Wellcome Trust. GS: SFHS is funded by the Scottish Executive Health Department, Chief Scientist Office, grant number CZD/16/6. Exome array genotyping for GS:SFHS was funded by the Medical Research Council UK and performed at the Wellcome Trust Clinical Research Facility Genetics Core at Western General Hospital, Edinburgh, UK. We acknowledge the invaluable contributions of the families who took part in the Generation Scotland: Scottish Family Health Study, the general practitioners and Scottish School of Primary Care for their help in recruiting them and the whole Generation Scotland team, which includes academic researchers, IT staff, laboratory technicians, statisticians and research managers. This study was financially supported by the Medical Research Fund of the Tampere University Hospital. S.R. was supported by the Academy of Finland (251217 and 255847), Center of Excellence in Complex Disease Genetics, EU FP7 projects ENGAGE (201413) and BioSHaRE (261433), the Finnish Foundation for Cardiovascular Research, Biocentrum Helsinki and the Sigrid Juselius Foundation. The KORA authors acknowledge all members of field staffs who were involved in the planning and conduction of the KORA Augsburg studies, as well as all KORA study participants. The KORA research platform (KORA, Cooperative Health Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. The KORA-Age project was financed by the German Federal Ministry of Education and Research (BMBF FKZ 01ET0713 and 01ET1003A) as part of the 'Health in old age' program. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. Further support was provided by the Competence Network ASCONET, subnetwork COSYCONET (FKZ 01GI0882). We thank the cohort participants who contributed to this study. Genotyping was supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC) (ref. BB/F019394/1). Phenotype collection was supported by Research Into Ageing (continues as part of Age UK's The Disconnected Mind project). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. We thank the late Professor Paula Rantakallio (launch of NFBC1966), and Ms Outi Tornwall and Ms MinttuJussila (DNA biobanking). NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194 and 24300796), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), EU FP7 (HEALTH-F4-2007-201413), EU FP8 (277849) and Medical Research Council, UK (G0500539, G1002319 and G0600705). U.G. acknowledges Swedish Medical Research Council (K2007-66X-20270-01-3, 2012-2884), Foundation for Strategic Research (SSF) and European Commission FP6 STRP (LSHG-CT-2006-01947). A.J.r acknowledges Swedish Society for Medical Research. The ORCADES study was funded by the Chief Scientist Office of the Scottish Government, the Royal Society and the MRC Human Genetics Unit. DNA extraction was performed at the Wellcome Trust Clinical Research Facility in Edinburgh. Genotyping was funded by the European Union Framework Programme 6 EUROSPAN project. Study directorate: NM Probst-Hensch (PI; e/g); T. Rochat (p), C. Schindler (s), N. Kunzli (e/exp), J.M. Gaspoz (c) Scientific team: J.C. Barthelemy (c), W. Berger (g), R. Bettschart (p), A. Bircher (a), C. Brombach (n), P.O. Bridevaux (p), L. Burdet (p), Felber Dietrich D. (e), M. Frey (p), U. Frey (pd), M.W. Gerbase (p), D. Gold (e), E. de Groot (c), W. Karrer (p), F. Kronenberg (g), B. Martin (pa), A. Mehta (e), D. Miedinger (o), M. Pons (p), F. Roche (c), T. Rothe (p), P. Schmid-Grendelmeyer (a), D. Stolz (p), A. Schmidt-Trucksass (pa), J. Schwartz (e), A. Turk (p), A. von Eckardstein (cc) and E. Zemp Stutz (e). Scientific team at coordinating centers: M. Adam (e), I. Aguilera (exp), S. Brunner (s), D. Carballo (c), S. Caviezel (pa), I. Curjuric (e), A. Di Pascale (s), J. Dratva (e), R. Ducret (s), E. Dupuis Lozeron (s), M. Eeftens (exp), I. Eze (e), E. Fischer (g), M. Foraster (e), M. Germond (s), L. Grize (s), S. Hansen (e), A. Hensel (s), M. Imboden (g), A. Ineichen (exp), A. Jeong (g), D. Keidel (s), A. Kumar (g), N. Maire (s), A. Mehta (e), R. Meier (exp), E. Schaffner (s), T. Schikowski (e) and M. Tsai (exp); (a) allergology, (c) cardiology, (cc) clinical chemistry, (e) epidemiology, (exp) exposure, (g) genetic and molecular biology, (m) meteorology, (n) nutrition, (o) occupational health, (p) pneumology, (pa) physical activity, (pd) pediatrics and (s) statistic. The study could not have been done without the help of the study participants, technical and administrative support and the medical teams and field workers at the local study sites. Local field workers: Aarau: S. Brun, G. Giger, M. Sperisen and M. Stahel; Basel: C. Burli, C. Dahler, N. Oertli, I. Harreh, F. Karrer, G. Novicic and N. Wyttenbacher; Davos: A. Saner, P. Senn and R. Winzeler; Geneva: F. Bonfils, B. Blicharz, C. Landolt and J. Rochat; Lugano: S. Boccia, E. Gehrig, M. T. Mandia, G. Solari and B. Viscardi; Montana: A. P. Bieri, C. Darioly and M. Maire; Payerne: F. Ding and P. Danieli A. Vonnez; Wald: D. Bodmer, E. Hochstrasser, R. Kunz, C. Meier, J. Rakic, U. Schafroth and A. Walder. Administrative staff: N. Bauer Ott, C. Gabriel, R. Gutknecht. Funding: The Swiss National Science Foundation (grants nos 33CS30-148470/1, 33CSCO-134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPDP3_129021/1 and PMPDP3_141671/1), the Federal Office for the Environment, the Federal Office of Public Health, the Federal Office of Roads and Transport, the Canton's Government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais and Zurich, the Swiss Lung League, the Canton's Lung League of Basel-Stadt/Basel Landschaft, Geneva, Ticino, Valais, Graubunden and Zurich, Stiftung ehemals Bundner Heilstatten, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), and Wellcome Trust WT 084703MA.r SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research, and the German Asthma and COPD Network (COSYCONET) (grant nos 01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A and BMBF 01GI0883). Genome-wide data have been supported by the Federal Ministry of Education and Research and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania (grant no. 03ZIK012). The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache 'Campus program of the InterSystems GmbH. We acknowledge the Academy of Finland (126925, 121584 and 124282), Academy of Finland (Eye) (134309), Academy of Finland (Salve) (129378), Academy of Finland (Gendi) (117787), Academy of Finland (Skidi) (41071), Social Insurance Institution of Finland, Tampere University Hospital Medical Funds (X51001 for T.L.), Kuopio University Hospital Medical Funds, Turku University Hospital Medical Funds, Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research (T.L.), Finnish Cultural Foundation, Tuberculosis Foundation (T.L.), Emil Aaltonen Foundation (T.L.) and Yrjo Jahnsson Foundation (T.L.). We are extremely grateful to all the families who took part in the study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (grant ref: 092731) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and D.M.E. will serve as guarantor for the contents of this paper. This work was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.P.S. and L.V.W. (MC_PC_12010). This research has been conducted using the UK Biobank Resource. M.D.T. has been supported by MRC fellowships G0501942 and G0902313. I.P.H. is supported by an MRC programme grant (G1000861). J.M. is funded by an ERC Consolidator Grant (617306). This article presents independent research funded partially by the NIHR. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We would like to acknowledge all members of the UK Biobank Array Design Group. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Peter Donnelly (chair) (University of Oxford), Jeff Barrett (Wellcome Trust Sanger Institute), Jose Bras (University College London), Adam Butterworth (University of Cambridge), Richard Durbin (Wellcome Trust Sanger Institute), Paul Elliott (Imperial College London), Ian Hall (University of Nottingham), John Hardy (University College London), Mark McCarthy (University of Oxford), Gil McVean (University of Oxford), Tim Peakman (UK Biobank), Nazneen Rahman (The Institute of Cancer Research), Nilesh Samani (University of Leicester), Martin Tobin (University of Leicester), Hugh Watkins (University of Oxford). We acknowledge EU funding (GABRIEL Grant Number: 018996, ECRHS II Coordination Number: QLK4-CT-1999-01237). A. P. M.r acknowledges the Wellcome Trust (WT098017, WT064890 and WT090532). The PIVUS study acknowledges The Swedish Foundation for Strategic Research (ICA08-0047), The Swedish Research Council (2012-1397), The Swedish Heart-Lung Foundation (20120197), The Swedish Society of Medicine and Uppsala University. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project p2013056. A. P. M. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). This cohort received funding from the Wellcome Trust; the European Community's Seventh Framework Programme (FP7/2007-13); US National Institutes of Health/National Eye Institute (1RO1EY018246); NIH Center for Inherited Disease Research; the NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. We thank the research staff at the Respiratory Health Network Tissue Bank of the FRQS for collecting lung specimens for the lung eQTL study at the Laval University. The Lung Tissue eQTL study was funded by Merck Research Laboratories. M.O. is a Post-doctoral Fellow of the Michael Smith Foundation for Health Research and the Canadian Institute for Health Research Integrated and Mentored Pulmonary and Cardiovascular Training program (IMPACT). Y.B. is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Quebec Sante (FRQS).