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 Burney; Sina 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

doi:10.1371/journal.pone.0147388

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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 language	English (US)
Article number	e0147388
Journal	PloS one
Volume	11
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0147388
State	Published - Feb 1 2016

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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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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), Article e0147388. https://doi.org/10.1371/journal.pone.0147388

Minelli, C, Dean, CH, Hind, M, Alves, AC, Amaral, AFS, Siroux, V, Huikari, V, Artigas, MS, Evans, DM, Loth, DW, Bossé, Y, Postma, DS, Sin, D, Thompson, J, Demenais, F, Henderson, J, Bouzigon, E, Jarvis, D, Järvelin, MR, 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, XQ, Trochet, H, Kähönen, M, Flexeder, C, Albrecht, E, Lopez, LM, De Jong, K, Thyagarajan, B, Enroth, S, Omenaas, E, Joshi, PK, Fall, T, Viñuela, 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, Pietiläinen, KH, Surakka, I, Liu, Y, Holliday, EG, Schulz, H, Heinrich, J, Davies, G, MVonk, J, Wojczynski, M, Pouta, A, Johansson, Å, Wild, SH, Ingelsson, E, Rivadeneira, F, Völzke, 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, YM, Redline, S, Jarvis, DL, Zhao, JH, Rantanen, T, O Connor, GT, Ripatti, S, Scott, RJ, Karrasch, S, Grallert, H, Gaddis, NC, MStarr, J, Wijmenga, C, Minster, RL, Lederer, DJ, Pekkanen, J, Gyllensten, U, Campbell, H, Morris, AP, Gläser, S, Hammond, CJ, MBurkart, K, Beilby, J, Kritchevsky, SB, Gudnason, V, Hancock, DB, Williams, OD, Polasek, O, Zemunik, T, Kolcic, I, Petrini, MF, Wjst, M, Kim, WJ, Porteous, DJ, Scotland, G, Smith, BH, Viljanen, A, Heliövaara, 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, Melén, E, Peters, MJ, Lange, LA, Barr, RG, Bracke, KR, MVerhamme, F, Sung, J, Hiemstra, PS, Cassano, PA, Sood, A, Hayward, C, Dupuis, J, Hall, IP, Brusselle, GG, Tobin, MD & London, SJ 2016, 'Association of Forced Vital Capacity with the Developmental Gene NCOR2', PloS one, vol. 11, no. 2, e0147388. https://doi.org/10.1371/journal.pone.0147388

@article{b0b9585b3a364da6baf7fd5e12ad14b6,

title = "Association of Forced Vital Capacity with the Developmental Gene NCOR2",

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.",

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

note = "Publisher Copyright: {\textcopyright} 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.",

year = "2016",

month = feb,

day = "1",

doi = "10.1371/journal.pone.0147388",

language = "English (US)",

volume = "11",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

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TY - JOUR

T1 - Association of Forced Vital Capacity with the Developmental Gene NCOR2

AU - Minelli, Cosetta

AU - Dean, Charlotte H.

AU - Hind, Matthew

AU - Alves, Alexessander Couto

AU - Amaral, André F S

AU - Siroux, Valerie

AU - Huikari, Ville

AU - Artigas, María Soler

AU - Evans, David M.

AU - Loth, Daan W.

AU - Bossé, Yohan

AU - Postma, Dirkje S.

AU - Sin, Don

AU - Thompson, John

AU - Demenais, Florence

AU - Henderson, John

AU - Bouzigon, Emmanuelle

AU - Jarvis, Deborah

AU - Järvelin, Marjo Riitta

AU - Burney, Peter

AU - Gharib, Sina A.

AU - Wain, Louise V.

AU - Franceschini, Nora

AU - Koch, Beate

AU - Pottinger, Tess D.

AU - Smith, Albert Vernon

AU - Duan, Qing

AU - Oldmeadow, Chris

AU - Lee, Mi Kyeong

AU - Strachan, David P.

AU - James, Alan L.

AU - Huffman, Jennifer E.

AU - Vitart, Veronique

AU - Ramasamy, Adaikalavan

AU - Wareham, Nicholas J.

AU - Kaprio, Jaakko

AU - Wang, Xin Qun

AU - Trochet, Holly

AU - Kähönen, Mika

AU - Flexeder, Claudia

AU - Albrecht, Eva

AU - Lopez, Lorna M.

AU - De Jong, Kim

AU - Thyagarajan, Bharat

AU - Enroth, Stefan

AU - Omenaas, Ernst

AU - Joshi, Peter K.

AU - Fall, Tove

AU - Viñuela, Ana

AU - Launer, Lenore J.

AU - Loehr, Laura R.

AU - Fornage, Myriam

AU - Li, Guo

AU - Wilk, Jemma B.

AU - Tang, Wenbo

AU - Manichaikul, Ani

AU - Lahousse, Lies

AU - Harris, Tamara B.

AU - North, Kari E.

AU - Rudnicka, Alicja R.

AU - Hui, Jennie

AU - Gu, Xiangjun

AU - Lumley, Thomas

AU - Wright, Alan F.

AU - Hastie, Nicholas D.

AU - Campbell, Susan

AU - Kumar, Rajesh

AU - Pin, Isabelle

AU - Scott, Robert A.

AU - Pietiläinen, Kirsi H.

AU - Surakka, Ida

AU - Liu, Yongmei

AU - Holliday, Elizabeth G.

AU - Schulz, Holger

AU - Heinrich, Joachim

AU - Davies, Gail

AU - MVonk, Judith

AU - Wojczynski, Mary

AU - Pouta, Anneli

AU - Johansson, Åsa

AU - Wild, Sarah H.

AU - Ingelsson, Erik

AU - Rivadeneira, Fernando

AU - Völzke, Henry

AU - Hysi, Pirro G.

AU - Eiriksdottir, Gudny

AU - Morrison, Alanna C.

AU - Rotter, Jerome I.

AU - Gao, Wei

AU - White, Wendy B.

AU - Rich, Stephen S.

AU - Hofman, Albert

AU - Aspelund, Thor

AU - Couper, David

AU - Smith, Lewis J.

AU - Psaty, Bruce M.

AU - Lohman, Kurt

AU - Burchard, Esteban G.

AU - Uitterlinden, André G.

AU - Garcia, Melissa

AU - Joubert, Bonnie R.

AU - McArdle, Wendy L.

AU - Musk, A. Bill

AU - Hansel, Nadia

AU - Heckbert, Susan R.

AU - Zgaga, Lina

AU - Van Meurs, Joyce B J

AU - Navarro, Pau

AU - Rudan, Igor

AU - Oh, Yeon Mok

AU - Redline, Susan

AU - Jarvis, Deborah L.

AU - Zhao, Jing Hua

AU - Rantanen, Taina

AU - O Connor, George T.

AU - Ripatti, Samuli

AU - Scott, Rodney J.

AU - Karrasch, Stefan

AU - Grallert, Harald

AU - Gaddis, Nathan C.

AU - MStarr, John

AU - Wijmenga, Cisca

AU - Minster, Ryan L.

AU - Lederer, David J.

AU - Pekkanen, Juha

AU - Gyllensten, Ulf

AU - Campbell, Harry

AU - Morris, Andrew P.

AU - Gläser, Sven

AU - Hammond, Christopher J.

AU - MBurkart, Kristin

AU - Beilby, John

AU - Kritchevsky, Stephen B.

AU - Gudnason, Vilmundur

AU - Hancock, Dana B.

AU - Williams, O'Dale

AU - Polasek, Ozren

AU - Zemunik, Tatijana

AU - Kolcic, Ivana

AU - Petrini, Marcy F.

AU - Wjst, Matthias

AU - Kim, Woo Jin

AU - Porteous, David J.

AU - Scotland, Generation

AU - Smith, Blair H.

AU - Viljanen, Anne

AU - Heliövaara, Markku

AU - Attia, John R.

AU - Sayers, Ian

AU - Hampel, Regina

AU - Gieger, Christian

AU - Deary, Ian J.

AU - Boezen, H. Marike

AU - Newman, Anne

AU - Wilson, James F.

AU - Lind, Lars

AU - Stricker, Bruno H.

AU - Teumer, Alexander

AU - Spector, Timothy D.

AU - Melén, Erik

AU - Peters, Marjolein J.

AU - Lange, Leslie A.

AU - Barr, R. Graham

AU - Bracke, Ken R.

AU - MVerhamme, Fien

AU - Sung, Joohon

AU - Hiemstra, Pieter S.

AU - Cassano, Patricia A.

AU - Sood, Akshay

AU - Hayward, Caroline

AU - Dupuis, Josée

AU - Hall, Ian P.

AU - Brusselle, Guy G.

AU - Tobin, Martin D.

AU - London, Stephanie J.

N1 - 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.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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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U2 - 10.1371/journal.pone.0147388

DO - 10.1371/journal.pone.0147388

M3 - Article

C2 - 26836265

AN - SCOPUS:84959440364

SN - 1932-6203

VL - 11

JO - PloS one

JF - PloS one

IS - 2

M1 - e0147388

ER -

Association of Forced Vital Capacity with the Developmental Gene NCOR2

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