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Lookup NU author(s): Dr Ana ViñuelaORCiD,
Dr Lenore Launer
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.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.
Author(s): Minelli C, Dean CH, Hind M, Alves AC, Amaral AFS, Siroux V, Huikari V, Artigas MS, Evans DM, Loth DW, Bosse Y, Postma DS, Sin D, Thompson J, Demenais F, Henderson J, Bouzigon E, Jarvis D, Jarvelin M-R, Burney P, Gharib SA, Wain LV, Franceschini N, Koch B, Pottinger TD, Smith AV, Duan Q, Oldmeadow C, Lee MK, Strachan DP, James AL, Huffman JE, Vitart V, Ramasamy A, Wareham NJ, Kaprio J, Wang X-Q, Trochet H, Kahonen M, Flexeder C, Albrecht E, Lopez LM, De Jong K, Thyagarajan B, Enroth S, Omenaas E, Joshi PK, Fall T, Vinuela A, Launer LJ, Loehr LR, Fornage M, Li G, Wilk JB, Tang W, Manichaikul A, Lahousse L, Harris TB, North KE, Rudnicka AR, Hui J, Gu X, Lumley T, Wright AF, Hastie ND, Campbell S, Kumar R, Pin I, Scott RA, Pietilainen KH, Surakka I, Liu Y, Holliday EG, Schulz H, Heinrich J, Davies G, Vonk JM, Wojczynski M, Pouta A, Johansson A, Wild SH, Ingelsson E, Rivadeneira F, Volzke H, Hysi PG, Eiriksdottir G, Morrison AC, Rotter JI, Gao W, White WB, Rich SS, Hofman A, Aspelund T, Couper D, Smith LJ, Psaty BM, Lohman K, Burchard EG, Uitterlinden AG, Garcia M, Joubert BR, McArdle WL, Musk AB, Hansel N, Heckbert SR, Zgaga L, Van Meurs JBJ, Navarro P, Rudan I, Oh Y-M, Redline S, Jarvis DL, Zhao JH, Rantanen T, O Connor GT, Ripatti S, Scott RJ, Karrasch S, Grallert H, Gaddis NC, Starr J, Wijmenga C, Minster RL, Lederer DJ, Pekkanen J, Gyllensten U, Campbell H, Morris AP, Glaser S, Hammond CJ, Burkart K, Beilby J, Kritchevsky SB, Gudnason V, Hancock DB, Williams O, Polasek O, Zemunik T, Kolcic I, Petrini MF, Wjst M, Kim WJ, Porteous DJ, Scotland G, Smith BH, Viljanen A, Heliovaara M, Attia JR, Sayers I, Hampel R, Gieger C, Deary IJ, Boezen HM, Newman A, Wilson JF, Lind L, Stricker BH, Teumer A, Spector TD, Melen E, Peters MJ, Lange LA, Barr RG, Bracke KR, Verhamme F, Sung J, Hiemstra PS, Cassano PA, Sood A, Hayward C, Dupuis J, Hall IP, Brusselle GG, Tobin MD, London SJ
Publication type: Article
Publication status: Published
Journal: PLoS ONE
Online publication date: 02/02/2016
Acceptance date: 04/01/2016
Date deposited: 01/07/2020
ISSN (electronic): 1932-6203
Publisher: Public Library of Science
PubMed id: 26836265
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