Association of Forced Vital Capacity with the Developmental Gene NCOR2

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  • Minelli, C.
    • Other Affiliation: Imperial College, London
  • Dean, C.H.
    • Other Affiliation: Imperial College, London
  • Hind, M.
    • Other Affiliation: Royal Brompton and Harefield NHS Foundation Trust
  • Alves, A.C.
    • Other Affiliation: Imperial College London
  • Amaral, A.F.S.
    • Other Affiliation: Imperial College, London
  • Siroux, V.
    • Other Affiliation: Univ. Grenoble Alpes
  • Huikari, V.
    • Other Affiliation: University of Oulu
  • Artigas, M.S.
    • Other Affiliation: University of Leicester
  • Evans, D.M.
    • Other Affiliation: University of Queensland Diamantina Institute
  • Loth, D.W.
    • Other Affiliation: Erasmus Medical Center
  • Bossé, Y.
    • Other Affiliation: Laval University
  • Postma, D.S.
    • Other Affiliation: University of Groningen
  • Sin, D.
    • Other Affiliation: St-Paul's Hospital
  • Thompson, J.
    • Other Affiliation: University of Leicester
  • Demenais, F.
    • Other Affiliation: Univ. Paris Diderot
  • Henderson, J.
    • Other Affiliation: University of Bristol
  • Bouzigon, E.
    • Other Affiliation: University of Leicester
  • Jarvis, D.
    • Other Affiliation: Imperial College London
  • Järvelin, M.-R.
    • Other Affiliation: Imperial College London
  • Burney, P.
    • Other Affiliation: Imperial College, London
  • Gharib, S.A.
    • Other Affiliation: University of Washington
  • Wain, L.V.
    • Other Affiliation: University of Leicester
  • Franceschini, N.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Koch, B.
    • Other Affiliation: University Hospital Greifswald
  • Pottinger, T.D.
    • Other Affiliation: Columbia University
  • Smith, A.V.
    • Other Affiliation: University of Iceland
  • Duan, Q.
    • Affiliation: School of Medicine, Department of Genetics
  • Oldmeadow, C.
    • Other Affiliation: University of Newcastle
  • Lee, M.K.
    • Other Affiliation: Seoul National University
  • Strachan, D.P.
    • Other Affiliation: University of London
  • James, A.L.
    • Other Affiliation: University of Western Australia
  • Huffman, J.E.
    • Other Affiliation: University of Edinburgh
  • Vitart, V.
    • Other Affiliation: University of Edinburgh
  • Ramasamy, A.
    • Other Affiliation: Imperial College London
  • Wareham, N.J.
    • Other Affiliation: Addenbrooke's Hospital
  • Kaprio, J.
    • Other Affiliation: University of Helsinki
  • Wang, X.-Q.
    • Other Affiliation: University of Virginia
  • Trochet, H.
    • Other Affiliation: University of Edinburgh
  • Kähönen, M.
    • Other Affiliation: University of Tampere
  • Flexeder, C.
    • Other Affiliation: Helmholtz Zentrum München German Research Center for Environmental Health
  • Albrecht, E.
    • Other Affiliation: Helmholtz Zentrum München German Research Center for Environmental Health
  • Lopez, L.M.
    • Other Affiliation: University of Edinburgh
  • De Jong, K.
    • Other Affiliation: University of Groningen
  • Thyagarajan, B.
    • Other Affiliation: University of Minnesota
  • Enroth, S.
    • Other Affiliation: Uppsala University
  • Omenaas, E.
    • Other Affiliation: University of Bergen
  • Joshi, P.K.
    • Other Affiliation: University of Edinburgh
  • Fall, T.
    • Other Affiliation: Uppsala University
  • Viñuela, A.
    • Other Affiliation: King's College London
  • Launer, L.J.
    • Other Affiliation: National Institutes of Health
  • Loehr, L.R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Fornage, M.
    • Other Affiliation: University of Texas Health Science Center at Houston
  • Li, G.
    • Other Affiliation: University of Washington
  • Wilk, J.B.
    • Other Affiliation: Pfizer Global Research and Development
  • Tang, W.
    • Other Affiliation: Cornell University
  • Manichaikul, A.
    • Other Affiliation: University of Virginia
  • Lahousse, L.
    • Other Affiliation: Ghent University Hospital
  • Harris, T.B.
    • Other Affiliation: National Institutes of Health
  • North, K.E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Rudnicka, A.R.
    • Other Affiliation: University of London
  • Hui, J.
    • Other Affiliation: PathWest Laboratory Medicine Washington
  • Gu, X.
    • Other Affiliation: University of Texas Health Science Center at Houston
  • Lumley, T.
    • Other Affiliation: University of Auckland
  • Wright, A.F.
    • Other Affiliation: University of Edinburgh
  • Hastie, N.D.
    • Other Affiliation: University of Edinburgh
  • Campbell, S.
    • Other Affiliation: University of Edinburgh
  • Kumar, R.
    • Other Affiliation: Northwestern University
  • Pin, I.
    • Other Affiliation: Université Joseph Fourier
  • Scott, R.A.
    • Other Affiliation: Addenbrooke's Hospital
  • Pietiläinen, K.H.
    • Other Affiliation: University of Helsinki,
  • Surakka, I.
    • Other Affiliation: University of Helsinki,
  • Liu, Y.
    • Other Affiliation: Wake Forest School of Medicine
  • Holliday, E.G.
    • Other Affiliation: University of Newcastle
  • Schulz, H.
    • Other Affiliation: Helmholtz Zentrum München
  • Heinrich, J.
    • Other Affiliation: Helmholtz Zentrum München
  • Davies, G.
    • Other Affiliation: University of Edinburgh
  • MVonk, J.
    • Other Affiliation: University of Groningen
  • Wojczynski, M.
    • Other Affiliation: Washington University, St. Louis
  • Pouta, A.
    • Other Affiliation: University of Oulu
  • Johansson, Å.
    • Other Affiliation: Uppsala University
  • Wild, S.H.
    • Other Affiliation: University of Edinburgh
  • Ingelsson, E.
    • Other Affiliation: Uppsala University
  • Rivadeneira, F.
    • Other Affiliation: Erasmus MC
  • Völzke, H.
    • Other Affiliation: University Medicine Greifswald
  • Hysi, P.G.
    • Other Affiliation: King's College London
  • Eiriksdottir, G.
    • Other Affiliation: Iceland Heart Association
  • Morrison, A.C.
    • Other Affiliation: University of Texas Health Science Center at Houston
  • Rotter, J.I.
    • Other Affiliation: Harbor-UCLA Medical Center
  • Gao, W.
    • Other Affiliation: Boston University
  • White, W.B.
    • Other Affiliation: Tougaloo College
  • Rich, S.S.
    • Other Affiliation: University of Virginia
  • Hofman, A.
    • Other Affiliation: Erasmus MC
  • Aspelund, T.
    • Other Affiliation: University of Iceland
  • Couper, D.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Smith, L.J.
    • Other Affiliation: Northwestern University
  • Psaty, B.M.
    • Other Affiliation: University of Washington
  • Lohman, K.
    • Other Affiliation: Wake Forest School of Medicine
  • Burchard, E.G.
    • Other Affiliation: University of California, San Francisco
  • Uitterlinden, A.G.
    • Other Affiliation: Erasmus MC
  • Garcia, M.
    • Other Affiliation: US National Institutes of Health
  • Joubert, B.R.
    • Other Affiliation: US National Institutes of Health
  • McArdle, W.L.
    • Other Affiliation: University of Bristol
  • Musk, A.B.
    • Other Affiliation: Sir Charles Gairdner Hospital
  • Hansel, N.
    • Other Affiliation: Johns Hopkins University
  • Heckbert, S.R.
    • Other Affiliation: Uppsala University
  • Zgaga, L.
    • Other Affiliation: Trinity College Dublin
  • Van Meurs, J.B.J.
    • Other Affiliation: Erasmus MC
  • Navarro, P.
    • Other Affiliation: University of Edinburgh
  • Rudan, I.
    • Other Affiliation: University of Edinburgh
  • Oh, Y.-M.
    • Other Affiliation: University of Ulsan College of Medicine
  • Redline, S.
    • Other Affiliation: Brigham and Women's Hospital
  • Jarvis, D.L.
    • Other Affiliation: Imperial College London
  • Zhao, J.H.
    • Other Affiliation: Addenbrooke's Hospital
  • Rantanen, T.
    • Other Affiliation: University of Jyväskylä
  • O'Connor, G.T.
    • Other Affiliation: Boston University
  • Ripatti, S.
    • Other Affiliation: University of Helsinki
  • Scott, R.J.
    • Other Affiliation: University of Newcastle
  • Karrasch, S.
    • Other Affiliation: National Institute for Health and Welfare
  • Grallert, H.
    • Other Affiliation: Helmholtz Zentrum München
  • Gaddis, N.C.
    • Other Affiliation: Research Triangle Institute International
  • MStarr, J.
    • Other Affiliation: University of Edinburgh
  • Wijmenga, C.
    • Other Affiliation: University of Groningen
  • Minster, R.L.
    • Other Affiliation: University of Pittsburgh
  • Lederer, D.J.
    • Other Affiliation: Columbia University
  • Pekkanen, J.
    • Other Affiliation: University of Eastern Finland
  • Gyllensten, U.
    • Other Affiliation: Uppsala University
  • Campbell, H.
    • Other Affiliation: University of Edinburgh
  • Morris, A.P.
    • Other Affiliation: University of Oxford
  • Gläser, S.
    • Other Affiliation: University Hospital Greifswald
  • Hammond, C.J.
    • Other Affiliation: King's College London
  • Burkart, K.M.
    • Other Affiliation: Columbia University
  • Beilby, J.
    • Other Affiliation: PathWest Laboratory Medicine Washington
  • Kritchevsky, S.B.
    • Other Affiliation: Wake Forest School of Medicine
  • Gudnason, V.
    • Other Affiliation: University of Iceland
  • Hancock, D.B.
    • Other Affiliation: US National Institutes of Health
  • Williams, O.
    • Other Affiliation: Florida International University
  • Polasek, O.
    • Other Affiliation: University of Split
  • Zemunik, T.
    • Other Affiliation: University of Split
  • Kolcic, I.
    • Other Affiliation: University of Split
  • Petrini, M.F.
    • Other Affiliation: University of Mississippi Medical Center
  • Wjst, M.
    • Other Affiliation: Helmholtz Zentrum München
  • Kim, W.J.
    • Other Affiliation: Kangwon National University
  • Porteous, D.J.
    • Other Affiliation: University of Edinburgh
  • Scotland, G.
    • Other Affiliation: University Medical Schools and National Health Service (NHS) in Aberdeen
  • Smith, B.H.
    • Other Affiliation: University of Dundee
  • Viljanen, A.
    • Other Affiliation: University of Jyväskylä
  • Heliövaara, M.
    • Other Affiliation: National Institute for Health and Welfare (THL)
  • Attia, J.R.
    • Other Affiliation: University of Newcastle
  • Sayers, I.
    • Other Affiliation: University of Nottingham
  • Hampel, R.
    • Other Affiliation: Helmholtz Zentrum München German Research Center for Environmental Health
  • Gieger, C.
    • Other Affiliation: Helmholtz Zentrum München
  • Deary, I.J.
    • Other Affiliation: University of Edinburgh
  • Boezen, H.M.
    • Other Affiliation: University of Groningen
  • Newman, A.
    • Other Affiliation: University of Pittsburgh
  • Wilson, J.F.
    • Other Affiliation: University of Edinburgh
  • Lind, L.
    • Other Affiliation: Uppsala University
  • Stricker, B.H.
    • Other Affiliation: Erasmus MC
  • Teumer, A.
    • Other Affiliation: University Medicine Greifswald
  • Spector, T.D.
    • Other Affiliation: King's College London
  • Melén, E.
    • Other Affiliation: Karolinska Institutet
  • Peters, M.J.
    • Other Affiliation: Erasmus MC
  • Lange, L.A.
    • Affiliation: School of Medicine, Department of Genetics
  • Barr, R.G.
    • Other Affiliation: Columbia University
  • Bracke, K.R.
    • Other Affiliation: Ghent University Hospital
  • MVerhamme, F.
    • Other Affiliation: Ghent University Hospital
  • Sung, J.
    • Other Affiliation: Seoul National University
  • Hiemstra, P.S.
    • Other Affiliation: Leiden University Medical Center
  • Cassano, P.A.
    • Other Affiliation: Cornell University
  • Sood, A.
    • Other Affiliation: University of New Mexico
  • Hayward, C.
    • Other Affiliation: University of Edinburgh
  • Dupuis, J.
    • Other Affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study
  • Hall, I.P.
    • Other Affiliation: University of Nottingham
  • Brusselle, G.G.
    • Other Affiliation: Ghent University Hospital
  • Tobin, M.D.
    • Other Affiliation: University of Leicester
  • London, S.J.
    • Other Affiliation: US National Institutes of Health
  • SpiroMeta consortium
  • CHARGE consortium.
Abstract
  • Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered as suggestive evidence. For SNPs with evidence of replication, effects on the expression levels of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium), with further functional investigation performed using public epigenomic profiling data (ENCODE). Results NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional enhancer element in lung fibroblasts, but its eQTL effects could not be tested due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated at nominal level only in adults (p = 0.026). The eQTL analyses showed association of WNT16-rs2707469 with expression levels of the nearby gene CPED1.We found no statistically significant eQTL effects for SERPINE2-rs6754561. Conclusions We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a role of Vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2, a COPD gene with weak previous evidence of association with FVC, and suggest WNT16 as a further promising candidate.
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DOI
Identifier
Resource type
  • Article
License
  • Attribution 4.0 International
Journal title
  • PLoS ONE
Journal volume
  • 11
Journal issue
  • 2
Language
  • English
Version
  • Publisher
Funder
  • Seventh Framework Programme, FP7: 201413, 277849, 633595
  • National Institutes of Health, NIH
  • European Regional Development Fund, ERDF
  • Servicio Andaluz de Salud, SAS
  • East Midlands Development Agency, EMDA
  • Sociedad Española de Neumología y Cirugía Torácica, SEPAR
  • National Institute of Mental Health, NIMH: 5R01MH63706:02, HEALTH-F4-2007-201413, RL1MH083268
  • National Institute for Health Research, NIHR
  • Université Laval, UL
  • European Commission, EC: 018996
  • Office Fédéral de l'Education et de la Science, OFES
  • National Heart and Lung Institute, NHLI
  • Cancer Research Society, CRS
  • Ministerio de Sanidad, Consumo y Bienestar Social, MISAN
  • Fonds de Recherche du Québec - Santé, FRQS
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF
  • Medical Research Council, MRC: G0500539, G0600705, G0901214, G1002319, G9815508, MC_PC_15018, MC_U106179471, MC_UU_12013/4, MC_UU_12015/1, MR/M022501/1
  • Fondation Institut Universitaire de Cardiologie et de Pneumologie de Québec, FIUCPQ
  • U.S. Public Health Service, USPHS: C03/011, C03/09, R01 HL62633-01
  • National Heart, Lung, and Blood Institute, NHLBI: 5R01HL087679-02, R01HL105756
  • Wellcome Trust, WT: 102215/2/13/2
  • Comissió Interdepartamental de Recerca i Innovació Tecnològica, CIRIT: 1997SGR 00079, 1999SGR 00241
  • SUVA
  • University of Bristol
  • Canadian Institutes of Health Research, CIHR: MOP—123369
  • 75617
  • Academy of Finland, AKA: 104781, 1114194, 120315, 129269, 24300796
  • 91/0016-060-05/E, 92/0319, 93/0393, 97/0035-01, 99/0034-01, 99/0034-02
  • Deutsche Forschungsgemeinschaft, DFG: 2610, FR 1526/1-1, MA 711/4-1
ISSN
  • 1932-6203
Publisher
  • Public Library of Science

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