Meta-analysis of exome array data identifies six novel genetic loci for lung function.pdf (1.14 MB)
Meta-analysis of exome array data identifies six novel genetic loci for lung function.
journal contribution
posted on 2019-08-30, 13:47 authored by VE Jackson, JC Latourelle, LV Wain, AV Smith, ML Grove, TM Bartz, M Obeidat, MA Province, W Gao, B Qaiser, DJ Porteous, PA Cassano, TS Ahluwalia, N Grarup, J Li, E Altmaier, J Marten, SE Harris, A Manichaikul, TD Pottinger, R Li-Gao, A Lind-Thomsen, A Mahajan, L Lahousse, M Imboden, A Teumer, B Prins, L-P Lyytikäinen, G Eiriksdottir, N Franceschini, CM Sitlani, JA Brody, Y Bossé, W Timens, A Kraja, A Loukola, W Tang, Y Liu, J Bork-Jensen, JM Justesen, A Linneberg, LA Lange, R Rawal, S Karrasch, JE Huffman, BH Smith, G Davies, KM Burkart, JC Mychaleckyj, TN Bonten, S Enroth, L Lind, GG Brusselle, A Kumar, B Stubbe, Understanding Society Scientific Group, M Kähönen, AB Wyss, BM Psaty, SR Heckbert, K Hao, T Rantanen, SB Kritchevsky, K Lohman, T Skaaby, C Pisinger, T Hansen, H Schulz, O Polasek, A Campbell, JM Starr, SS Rich, DO Mook-Kanamori, Å Johansson, E Ingelsson, AG Uitterlinden, S Weiss, OT Raitakari, V Gudnason, KE North, SA Gharib, DD Sin, KD Taylor, GT O'Connor, J Kaprio, TB Harris, O Pederson, H Vestergaard, JG Wilson, K Strauch, C Hayward, S Kerr, IJ Deary, RG Barr, R de Mutsert, U Gyllensten, AP Morris, MA Ikram, N Probst-Hensch, S Gläser, E Zeggini, T Lehtimäki, DP Strachan, J Dupuis, AC Morrison, IP Hall, MD Tobin, SJ LondonBackground: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Funding
This article presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. MDT has been supported by Medical Research Council (MRC) fellowships G0501942 and G0902313. MDT and LVW are supported by the MRC (MR/N011317/1). IPH is supported by the MRC (G1000861). ALW and SJL are supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES 043012). We acknowledge use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the MRC (G0000934) and the Wellcome Trust (068545). APM was a Wellcome Trust Senior Fellow in Basic Biomedical Science (098017) and was also supported by Wellcome Trust grant 064890. EI is supported by the Swedish Research Council (2012-1397), Knut och Alice Wallenberg Foundation (2013.0126) and the Swedish Heart-Lung Foundation (20140422). JK is supported by Academy of Finland Center of Excellence in Complex Disease Genetics (213506, 129680) and Academy of Finland (265240, 263278). The Finnish Twin Cohort is supported by the Welcome Trust Sanger Institute, UK. The Lothian Birth Cohort is supported by Age UK (The Disconnected Mind Project), the MRC (MR/K026992/1) and The Royal Society of Edinburgh. ÅJ is supported by the Swedish Society for Medical Research, The Kjell och Märta Beijers Foundation, The Marcus Borgström Foundation, The Åke Wiberg foundation and The Vleugels Foundation. UG is supported by Swedish Medical Research Council (K2007-66X-20270-01-3, 2011-2354) and European Commission FP6 (LSHG-CT-2006-01947). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the n
History
Citation
Wellcome Open Research, 2018, 3:4Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/Themes/Respiratory ScienceVersion
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