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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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.

Original languageEnglish (US)
Article numbere0147388
JournalPloS one
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2016

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    Minelli, C., Dean, C. H., Hind, M., Alves, A. C., Amaral, A. F. S., Siroux, V., Huikari, V., Artigas, M. S., Evans, D. M., Loth, D. W., Bossé, Y., Postma, D. S., Sin, D., Thompson, J., Demenais, F., Henderson, J., Bouzigon, E., Jarvis, D., Järvelin, M. R., ... London, S. J. (2016). Association of Forced Vital Capacity with the Developmental Gene NCOR2. PloS one, 11(2), [e0147388]. https://doi.org/10.1371/journal.pone.0147388