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.
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
authors.affiliation: Leukocyte Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.|Mammalian Genetics Unit, MRC Harwell, Oxon, United Kingdom.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Dean
authors.affiliation: Respiratory Department, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hind
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Alexessander Couto
authors.initials: AC
authors.lastname: Alves
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, United Kingdom.|MRC-PHE Centre for Environment & Health, London, United Kingdom.
authors.forename: André F S
authors.initials: AF
authors.lastname: Amaral
authors.affiliation: Univ. Grenoble Alpes, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, F-38000, Grenoble, France.|INSERM, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, F-38000, Grenoble, France.|CHU de Grenoble, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, F-38000, Grenoble, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Siroux
authors.affiliation: Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Huikari
authors.affiliation: Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: María
authors.initials: M
authors.lastname: Soler Artigas
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Daan W
authors.initials: DW
authors.lastname: Loth
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: The University of British Columbia Center for Heart Lung Innovation, St-Paul's Hospital, Vancouver, Canada.
authors.forename: Don
authors.initials: D
authors.lastname: Sin
authors.affiliation: Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Thompson
authors.affiliation: INSERM, UMRS-946, Genetic Variation of Human Diseases Unit, Paris, France.|Univ. Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F-75007, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Henderson
authors.affiliation: INSERM, UMRS-946, Genetic Variation of Human Diseases Unit, Paris, France.|Univ. Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F-75007, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bouzigon
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, United Kingdom.|MRC-PHE Centre for Environment & Health, London, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Jarvis
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.|MRC-PHE Centre for Environment & Health, London, United Kingdom.|Biocenter Oulu, University of Oulu, Oulu, Finland.|Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, FI-90014 University of Oulu, Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, FI-90220, Oulu, 90029 OYS, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, United Kingdom.|MRC-PHE Centre for Environment & Health, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Burney
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics*; D020869:Gene Expression Profiling; D050437:Genes, Developmental; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000196:embryology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D055815:Young Adult
chemical_list: D056985:Nuclear Receptor Co-Repressor 2
references.citation: Nat Genet. 2014 Jul;46(7):669-77
references.pmid: 24929828
references.citation: Int J Epidemiol. 2013 Feb;42(1):111-27
references.pmid: 22507743
references.citation: N Engl J Med. 2010 May 13;362(19):1829-31
references.pmid: 20463343
references.citation: Eur Respir J. 1998 Sep;12(3):627-34
references.pmid: 9762791
references.citation: Nature. 2007 Jun 14;447(7146):799-816
references.pmid: 17571346
references.citation: J Allergy Clin Immunol. 2014 Nov;134(5):1036-42.e15
references.pmid: 24857373
references.citation: Stat Sci. 2009 Nov 1;24(4):414-429
references.pmid: 20607129
references.citation: G3 (Bethesda). 2013 Nov;3(11):1881-91
references.pmid: 24002865
references.citation: Nat Genet. 2008 Feb;40(2):124-5
references.pmid: 18227866
references.citation: Respir Res. 2010;11:92
references.pmid: 20604964
references.citation: Eur Respir J. 2001 Apr;17(4):696-702
references.pmid: 11401066
references.citation: N Engl J Med. 2010 May 13;362(19):1784-94
references.pmid: 20463338
references.citation: Chest. 2011 Sep;140(3):667-74
references.pmid: 21436250
references.citation: Genome Med. 2014 Oct 28;6(10):85
references.pmid: 25473424
references.citation: Organogenesis. 2011 Jul-Sep;7(3):209-16
references.pmid: 22030785
references.citation: Thorax. 2013 Apr;68(4):380-4
references.pmid: 22781122
references.citation: Thorax. 2011 Jan;66(1):49-54
references.pmid: 20980245
references.citation: Nat Genet. 2007 Jul;39(7):906-13
references.pmid: 17572673
references.citation: Thorax. 2009 May;64(5):451-7
references.pmid: 19401491
references.citation: Genome Biol. 2009;10(11):R130
references.pmid: 19919682
references.citation: Cancer Res. 2009 Dec 15;69(24):9183-91
references.pmid: 19951988
references.citation: Nat Rev Mol Cell Biol. 2015 Feb;16(2):110-23
references.pmid: 25560970
references.citation: PLoS Genet. 2012;8(11):e1003029
references.pmid: 23209423
references.citation: Clin Exp Allergy. 1999 Dec;29 Suppl 4:17-21
references.pmid: 10641560
references.citation: Chest. 2007 Aug;132(2):651-6
references.pmid: 17699136
references.citation: Am J Hum Genet. 2006 Feb;78(2):253-64
references.pmid: 16358219
references.citation: N Engl J Med. 2006 Jul 6;355(1):21-30
references.pmid: 16822993
references.citation: Science. 2009 Sep 4;325(5945):1246-50
references.pmid: 19644074
references.citation: Am J Epidemiol. 2012 Jan 1;175(1):33-42
references.pmid: 22138040
references.citation: Nat Genet. 2011 Nov;43(11):1082-90
references.pmid: 21946350
references.citation: Paediatr Perinat Epidemiol. 1988 Jan;2(1):59-88
references.pmid: 2976931
references.citation: Eur Respir J. 1994 May;7(5):954-60
references.pmid: 8050554
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D109-14
references.pmid: 22080510
references.citation: Dev Cell. 2010 Jan 19;18(1):8-23
references.pmid: 20152174
references.citation: Nat Genet. 2010 Jan;42(1):45-52
references.pmid: 20010835
references.citation: Am J Respir Cell Mol Biol. 2009 Jan;40(1):47-57
references.pmid: 18664640
references.citation: Eur Respir J. 2013 Mar;41(3):756-7
references.pmid: 23456936
references.citation: Chest. 2007 Nov;132(5):1608-14
references.pmid: 17998360
references.citation: J Allergy Clin Immunol. 2014 Jan;133(1):68-76.e1-4
references.pmid: 23886569
references.citation: Front Genet. 2013 Sep 09;4:174
references.pmid: 24058366
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520