Abstract
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
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Acknowledgements
We thank the many colleagues who contributed to collection and phenotypic characterization of the clinical sampling, genotyping and analysis of the GWAS data. We especially thank those who kindly agreed to participate in the studies.
Major funding for this work is from the following sources (in alphabetical order): Academy of Finland (including project grants 104781, 120315 and 1114194) and Center of Excellence in Complex Disease Genetics; Arthritis Research Campaign; Asthma UK; AstraZeneca; Biocenter Oulu, University of Oulu; Biocentrum Helsinki; Biotechnology and Biological Sciences Research Council project grant; British Heart Foundation (including project grants PG/06/154/22043 and PG/97012 and Senior Research Fellowship FS05/125); British Lung Foundation; Cancer Research United Kingdom; Chief Scientists Office, part of the Scottish Government Health Directorate (including grant CZD/16/6); Department of Health Air Pollution PRP (ref. no. 0020029); ENGAGE project (HEALTH-F4-2007-201413); European Commission (EURO-BLCS, FP-5/QLG1-CT-2000-01643, FP-7/2007-2013, FP-6 LSHB-CT-2006-018996 (GABRIEL), FP-6 LSHG-CT-2006-01947 (EUROSPAN), HEALTH-F2-2008-201865-GEFOS and FP-5 GenomEUtwin project QLG2-CT-2002-01254); Finnish Ministry of Education; German Federal Ministry of Education and Research (BMBF, including grants 01ZZ96030, 01ZZ0701 and 01GI0883 and German Asthma and COPD Network (COSYCONET) grant 01GI0883); German Ministry for Education, Research and Cultural Affairs; German National Genome Research Network (NGFN-2 and NGFN-plus); Healthway, Western Australia; HEFCE Science Research Investment Fund; Helmholtz Zentrum München; German Research Center for Environmental Health, Neuherberg, Germany; International Osteoporosis Foundation; Juvenile Diabetes Research Foundation International; Leicester Biomedical Research Unit in Cardiovascular Science (NIHR); Medical Research Council UK (including grants G0500539, G0501942, G0000943 and G990146); Medical Research Fund of the Tampere University Hospital; Ministry for Social Affairs of the Federal State of Mecklenburg-West Pomerania; MRC Human Genetics Unit; Munich Center of Health Sciences, as part of LMUinnovativ; National Human Genome Research Institute; National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute (grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)); Oulu University Hospital; PHOEBE (FP6, LSHG-CT-2006-518418); Public Population Project in Genomics (Genome Canada and Genome Quebec), Republic of Croatia Ministry of Science, Education and Sports (research grant 108-1080315-0302); Royal Society; Siemens Health Care Sector; Swedish Heart and Lung Foundation (grant 20050561); Swedish Medical Research Council (project no. K2007-66X-20270-01-3); Swedish Research Council for Working Life and Social Research (FAS, grants 2001-0263 and 2003-0139); the Great Wine Estates of the Margaret River region of Western Australia; UBS Wealth Foundation (grant BA29s8Q7-DZZ); UK Department of Health Policy Research Programme; University of Nottingham; University of Bristol; US National Institutes of Health (U01 DK062418); US National Institutes of Health–National Institute of Mental Health (5R01MH63706:02); Wellcome Trust (including grants 068545/Z/02, 076113/B/04/Z, 079895, 077016/Z/05/Z, 075883 and 086160/Z/08/A); and Zentren für Innovationskompetenz (BMBF grant 03ZIK012).
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Authors and Affiliations
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Contributions
Author contributions are listed in alphabetical order. See Table 1 for definitions of study acronyms.
Project conception, design and management. Stage 1 GWAS, ALSPAC: J. Henderson, R.G. B58C: D.P.S. EPIC: I.B., R.J.F.L., N.J.W., J.H.Z. FTC: J.K., T.R. KORA S3: H.E.W. Korcula: H.C., I.G., S.J., I.R., A.F.W., L.Z. NFBC1966: P.E., M.-R.J., A.P., L.P. NSPHS: U.G. ORCADES: H.C., S.H.W., J.F.W., A.F.W. SHIP: S.G., G.H., B.K., H.V. TwinsUK: T.D.S., G. Zhai. Vis: H.C., C.H., O.P., I.R., A.F.W. Stage 2a follow-up, ADONIX: A.-C.O., K.T. BHS: A.L.J., L.J.P. GS:SFHS: H.C., C.J., A.D.M., D.J.P. HCS: C.C., E.D., J.W.H. KORA F4: S.K, E.S., H.S. NFBC1986: A.-L.H., M.-R.J. Nottingham Smokers: I.P.H., I. Sayers, M.O. NSHD: The NSHD Respiratory Study Team. Stage 2b in silico follow-up, Health 2000: M.H., M.K., L.P.
Phenotype collection and data management. Stage 1 GWAS, ALSPAC: J. Henderson, R.G. B58C: D.P.S., A.R.R. EPIC: N.J.W. FTC: J.K., L.M., T.R. KORA S3: H.E.W. Korcula: I.G., S.J., O.P., I.R., L.Z. NFBC1966: P.E., M.-R.J., A.-L.H., A.P. NSPHS: G. Zaboli. ORCADES: H.C., S.H.W., J.F.W. SHIP: S.G., B.K., H.V. TwinsUK: M.M., T.D.S. Vis: H.C., C.H., O.P., I.R., A.F.W. Stage 2a follow-up, ADONIX: A.-C.O., K.T. BHS: M.N.C., A.L.J., L.J.P. BRHS: R.W.M., S.G.W., P.H.W. BWHHS: G.D.S., S.E., D.A.L., P.H.W. Gedling: J.R.B., T.M.M., I.D.P. GS:SFHS: C.J., D.J.P. HCS: C.C., E.D., S.S. KORA F4: S.K., E.S., H.S. NFBC1986: A.-L.H., M.-R.J. Nottingham Smokers: J.D.B., I.P.H., I. Sayers, M.O. NSHD: The NSHD Respiratory Study Team. Stage 2b in silico follow-up, Health 2000: M.H., M.K.
Genotyping. Stage 1 GWAS, ALSPAC: P.D. B58C: W.L.M., WTCCC. EPIC: I.B., R.J.F.L., N.J.W., J.H.Z. FTC: J.K., I. Surakka. KORA S3: M.I., N.M.P.-H., H.G. NFBC1966: P.E., M.-R.J., L.P. ORCADES: H.C., J.F.W. SHIP: G.H. TwinsUK: N.S. Vis: C.H., I.R., A.F.W. Stage 2a follow-up, ADONIX: A.T.N., F.N. BRHS: A.D.H., R.W.M., P.H.W. GS:SFHS: A.D.M. HCS: C.C., E.D., J.W.H. KORA F4: H.G. NFBC1986: N.B.-N., J.D., P.F., M.-R.J., L.P. Nottingham Smokers: I.P.H. NSHD: D.K., A.W. STAGE 2b in silico follow-up, Health 2000: L.P., S.R., I. Surakka.
Data analysis. Stage 1 GWAS, ALSPAC: D.M.E. B58C: A.R.R. EPIC: R.J.F.L., J.H.Z. FTC: I. Surakka., L.M. KORA S3: E.A., M.I., N.M.P.-H. Korcula: C.H., J.E.H., V.V. NFBC1966: A.R. NSPHS: W.I., A.J. ORCADES: C.H., V.V. SHIP: S.G., G.H., B.K, H.V. TwinsUK: G. Zhai. Vis: C.H., V.V. Stage 2a follow-up, ADONIX: A.T.N., F.N., A.-C.O, K.T. BHS: M.N.C., J. Hui., L.J.P. BRHS: R.W.M. BWHHS: D.A.L. Gedling: M.O., M.D.T. GS:SFHS: A.K.M. HCS: J.W.H., S.S. KORA F4: E.A, H.G. NFBC1986: A.R. Nottingham Smokers: M.O., I. Sayers, M.D.T. NSHD: The NSHD Respiratory Study Team. Stage 2b in silico follow-up, Health 2000: M.K., S.R., I. Surakka.
Meta-analysis group. P.R.B., I.P.H., T.J., E.R., D.P.S., M.D.T., L.V.W.
Bioinformatics and expression profiling groups. I.P.H., M.O., I. Sayers, E.R., M.D.T., L.V.W.
Writing group. P.E., I.P.H., E.R., I. Sayers, D.P.S., M.D.T., L.V.W.
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I.B. and spouse own stock in GlaxoSmithKline and Incyte.
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A full list of members is provided in the Supplementary Note.
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Supplementary Text and Figures
Supplementary Figures 1 and 2, Supplementary Tables 1–4 and 6 and Supplementary Note (PDF 1193 kb)
Supplementary Table 5
List of the top 2000 SNPs for association with FEV1 and FEV1/FVC (XLS 356 kb)
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Repapi, E., Sayers, I., Wain, L. et al. Genome-wide association study identifies five loci associated with lung function. Nat Genet 42, 36–44 (2010). https://doi.org/10.1038/ng.501
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DOI: https://doi.org/10.1038/ng.501
