Association of Forced Vital Capacity with the Developmental Gene NCOR2

Cosetta Minelli, Charlotte H. Dean, Matthew Hind, Alexessander Couto Alves, André F S Amaral, Valerie Siroux, Ville Huikari, María Soler Artigas, David M. Evans, Daan W. Loth, Yohan Bossé, Dirkje S. Postma, Don Sin, John Thompson, Florence Demenais, John Henderson, Emmanuelle Bouzigon, Deborah Jarvis, Marjo Riitta Järvelin, Peter BurneySina A. Gharib, Louise V. Wain, Nora Franceschini, Beate Koch, Tess D. Pottinger, Albert Vernon Smith, Qing Duan, Chris Oldmeadow, Mi Kyeong Lee, David P. Strachan, Alan L. James, Jennifer E. Huffman, Veronique Vitart, Adaikalavan Ramasamy, Nicholas J. Wareham, Jaakko Kaprio, Xin Qun Wang, Holly Trochet, Mika Kähönen, Claudia Flexeder, Eva Albrecht, Lorna M. Lopez, Kim De Jong, Bharat Thyagarajan, Stefan Enroth, Ernst Omenaas, Peter K. Joshi, Tove Fall, Ana Viñuela, Lenore J. Launer, Laura R. Loehr, Myriam Fornage, Guo Li, Jemma B. Wilk, Wenbo Tang, Ani Manichaikul, Lies Lahousse, Tamara B. Harris, Kari E. North, Alicja R. Rudnicka, Jennie Hui, Xiangjun Gu, Thomas Lumley, Alan F. Wright, Nicholas D. Hastie, Susan Campbell, Rajesh Kumar, Isabelle Pin, Robert A. Scott, Kirsi H. Pietiläinen, Ida Surakka, Yongmei Liu, Elizabeth G. Holliday, Holger Schulz, Joachim Heinrich, Gail Davies, Judith MVonk, Mary Wojczynski, Anneli Pouta, Åsa Johansson, Sarah H. Wild, Erik Ingelsson, Fernando Rivadeneira, Henry Völzke, Pirro G. Hysi, Gudny Eiriksdottir, Alanna C. Morrison, Jerome I. Rotter, Wei Gao, Wendy B. White, Stephen S. Rich, Albert Hofman, Thor Aspelund, David Couper, Lewis J. Smith, Bruce M. Psaty, Kurt Lohman, Esteban G. Burchard, André G. Uitterlinden, Melissa Garcia, Bonnie R. Joubert, Wendy L. McArdle, A. Bill Musk, Nadia Hansel, Susan R. Heckbert, Lina Zgaga, Joyce B J Van Meurs, Pau Navarro, Igor Rudan, Yeon Mok Oh, Susan Redline, Deborah L. Jarvis, Jing Hua Zhao, Taina Rantanen, George T. O Connor, Samuli Ripatti, Rodney J. Scott, Stefan Karrasch, Harald Grallert, Nathan C. Gaddis, John MStarr, Cisca Wijmenga, Ryan L. Minster, David J. Lederer, Juha Pekkanen, Ulf Gyllensten, Harry Campbell, Andrew P. Morris, Sven Gläser, Christopher J. Hammond, Kristin MBurkart, John Beilby, Stephen B. Kritchevsky, Vilmundur Gudnason, Dana B. Hancock, O'Dale Williams, Ozren Polasek, Tatijana Zemunik, Ivana Kolcic, Marcy F. Petrini, Matthias Wjst, Woo Jin Kim, David J. Porteous, Generation Scotland, Blair H. Smith, Anne Viljanen, Markku Heliövaara, John R. Attia, Ian Sayers, Regina Hampel, Christian Gieger, Ian J. Deary, H. Marike Boezen, Anne Newman, James F. Wilson, Lars Lind, Bruno H. Stricker, Alexander Teumer, Timothy D. Spector, Erik Melén, Marjolein J. Peters, Leslie A. Lange, R. Graham Barr, Ken R. Bracke, Fien MVerhamme, Joohon Sung, Pieter S. Hiemstra, Patricia A. Cassano, Akshay Sood, Caroline Hayward, Josée Dupuis, Ian P. Hall, Guy G. Brusselle, Martin D. Tobin, Stephanie J. London

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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.

Original languageEnglish (US)
Article numbere0147388
JournalPloS one
Issue number2
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
This work was supported by a contract from the European Commission (018996), Fondo de Investigación Sanitaria (91/0016-060-05/E, 92/0319, 93/0393, 97/0035-01, 99/0034-01 and 99/0034-02), Hospital General de Albacete, Hospital General Ramón Jiménez, Consejería de Sanidad del Principado de Asturias, CIRIT (1997SGR 00079, 1999SGR 00241), and Servicio Andaluz de Salud, SEPAR, Public Health Service (R01 HL62633-01), RCESP (C03/09), Red RESPIRA (C03/011), Basque Health Department, Swiss National Science Foundation, Swiss Federal Office for Education and Science, Swiss National Accident Insurance Fund (SUVA), GSF-National Research Centre for Environment and Health, Deutsche Forschungsgemeinschaft (DFG) (FR 1526/1-1, MA 711/4-1), Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, Ministere de l’Emploi et de la Solidarite, Direction Generale de la Sante, CHU de Grenoble, Comite des Maladies Respiratoires de l’Isere. UCB-Pharma (France), Aventis (France), Glaxo France. Estonian Science Foundation. AsthmaUK (formerly known as National Asthma Campaign UK).

Funding Information:
The Lung eQTL study : The authors would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL dataset at Laval University. The lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fondation JD Bégin de l’Université Laval, the Fondation de l’Institut universitaire de cardiologie et de pneumologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP—123369), and the Cancer Research Society and Read for the Cure. Y. Bossé is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Québec–Santé (FRQS). At the Groningen UMCG site Marnix Jonker is thanked for his support in selecting, handling and sending of lung tissues.

Funding Information:
SpiroMeta consortium : The research undertaken by MSA was part-funded 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. 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 (EMDA), part-financed by the European Regional Development Fund and delivered by Medilink East Midlands. Contact: Martin D Tobin ( )

Funding Information:
NFBC1966 study : NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing -277849, the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and the MRC, Centenary Early Career Award. The program is currently being funded by the H2020-633595 DynaHEALTH action and academy of Finland EGEA-project.

Funding Information:
CHARGE consortium : Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. Contact: Stephanie J London ( )

Funding Information:
ALSPAC study : We are extremely grateful to all the families who took part in this 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. GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corportation of America) using support from 23andMe. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and DME and AJH will serve as guarantors for the contents of this paper.

Publisher Copyright:
© 2016 Minelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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