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2024
article
Association of Forced Vital Capacity with the Developmental Gene NCOR2
Pieter S. Hiemstra, Lies Lahousse, Henry Völzke, K. De Jong, Thor Aspelund, G. Eiríksdóttir, Antonio Viñuela, Vilmundur Guðnason, Ian P. Hall, Tatijana Zemunik, B. Koch, S.R. Heckbert, Cisca Wijmenga, F. Rivadeneira, Lizbeeth Lopez, Xiaoqiong Gu, O. Polasek, J.E. Huffman, A. Manichaikul, Erik Melén, Claudia Flexeder, S. Ripatti, Wendy White, T.B. Harris, P. Navarro, W.H. Wilson Tang, Mika Kähönen, J.I. Rotter, Rajesh Kumar, X.-Q. Wang, Alicja R. Rudnicka, D.S. Postma, Anil K. Sood, Ernst Omenaas, B.M. Psaty, Generation Scotland, Guixia Li, Kristin M. Burkart, Ville Huikari, Nicholas D. Hastie, Juha Pekkanen, Lewis J. Smith, María Soler Artigas, Adaikalavan Ramasamy, Laura R. Loehr, M.K. Lee, R Hampel, Ann Valentine Smith, Jennie Hui, Pirro G. Hysi, L.A. Lange, David Couper, Markku Heliövaara, L.J. Launer, Don D. Sin, G. Davies, Tess D. Pottinger, Ivana Kolčić, R. Graham Barr, Mark Peters, Yohan Bossé, I.J. Deary, Andrea Hofman, CHARGE Consortium, Ryan L. Minster, Ken R. Bracke, Alexessander Couto Alves, SH Wild, E. Albrecht, D P Strachan, S.S. Rich, Christian Gieger, Åsa Johansson, I. Rudan, N. Franceschini, Dana B. Hancock, Marjo‐Riitta Järvelin, Stephen B. Kritchevsky, J. Attia, Esteban Burchard, Martin D. Tobin, J. Dupuis, Stephanie J. London, John Beilby, Abigail Wright, H. Grallert, Steve Gläser, Susan Redline, A. Pouta, Lina Zgaga, A.C. Morrison, Valérie Siroux, D.J. Lederer, Guy Brusselle, Anne Viljanen, Stefan Karrasch, A.B. Musk, Q. Duan, L. Lind, Wei Gao, Nathan Gaddis, Yeon‐Mok Oh, E.G. Holliday, Anne B. Newman, Kirsi H. Pietiläinen, J.F. Wilson, Thomas Lumley, A.G. Uitterlinden, Véronique Vitart, N.J. Wareham, Cosetta Minelli, Y. Liu, Mary K. Wojczynski, R.A. Scott, Rodney J. Scott, Florence Démenais, B.H. Stricker, Bonnie R. Joubert, J. MVonk, David J. Porteous, Matthew Hind, George O'connor, André F.S. Amaral, J. MStarr, Joohon Sung, L.V. Wain, Taina Rantanen, H. Campbell, I. Pin, C. Hayward, Sina A. Gharib, Jaakko Kaprio, E. Ingelsson, Woo Jin Kim, J. Heinrich, Anthony James, Jianhua Zhao, Tove Fall, Jemma B. Wilk, Owen Martin Williams, Peter Burney, Ian Sayers, David M. Evans, H. Schulz, S Campbell, Holly Trochet, Ulf Gyllensten, Wendy L. McArdle, Alexander Teumer, P.K. Joshi, A.P. Morris, Daan W. Loth, K.E. North, Deborah Jarvis, SpiroMeta Consortium, Joyce B. J. van Meurs, M Wjst, Charlotte Dean, Stefan Enroth, Nadia N. Hansel, John Henderson, Christopher Oldmeadow, M. Fornage, Christopher J. Hammond, Marcy F. Petrini, T.D. Spector, Emmanuelle Bouzigon, B. Thyagarajan, Patricia A. Cassano, H.M. Boezen, Ida Surakka, John R. Thompson, Melissa Garcia, F. MVerhamme, Blair H. Smith, Kurt Lohman
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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.
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