Abstract
Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/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.
Original language | English |
---|---|
Article number | 4 |
Number of pages | 28 |
Journal | Wellcome Open Research |
Volume | 3 |
DOIs | |
Publication status | Published - 7 Aug 2018 |
Keywords
- Lung function
- respiratory
- exome array
- GWAS
- COPD
ASJC Scopus subject areas
- Medicine (miscellaneous)
- General Biochemistry,Genetics and Molecular Biology
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In: Wellcome Open Research, Vol. 3, 4, 07.08.2018.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function
AU - Understanding Society Scientific Group
AU - Jackson, Victoria E.
AU - Latourelle, Jeanne C.
AU - Wain, Louise V.
AU - Smith, Albert V.
AU - Grove, Megan L.
AU - Bartz, Traci M.
AU - Obeidat, Ma'en
AU - Province, Michael A.
AU - Gao, Wei
AU - Qaiser, Beenish
AU - Porteous, David J.
AU - Cassano, Patricia A.
AU - Ahluwalia, Tarunveer S.
AU - Grarup, Niels
AU - Li, Jin
AU - Altmaier, Elisabeth
AU - Marten, Jonathan
AU - Harris, Sarah E.
AU - Manichaikul, Ani
AU - Pottinger, Tess D.
AU - Li-Gao, Ruifang
AU - Lind-Thomsen, Allan
AU - Mahajan, Anubha
AU - Lahousse, Lies
AU - Imboden, Medea
AU - Teumer, Alexander
AU - Prins, Bram
AU - Lyytikäinen, Leo-Pekka
AU - Eiriksdottir, Gudny
AU - Franceschini, Nora
AU - Sitlani, Colleen M.
AU - Brody, Jennifer A.
AU - Bossé, Yohan
AU - Timens, Wim
AU - Kraja, Aldi
AU - Loukola, Anu
AU - Tang, Wenbo
AU - Liu, Yongmei
AU - Bork-Jensen, Jette
AU - Justesen, Johanne M.
AU - Linneberg, Allan
AU - Lange, Leslie A.
AU - Rawal, Rajesh
AU - Karrasch, Stefan
AU - Huffman, Jennifer E.
AU - Smith, Blair H.
AU - Davies, Gail
AU - Burkart, Kristin M.
AU - Mychaleckyj, Josyf C.
AU - Morris, Andrew P.
AU - Tobin, Martin D.
AU - London, Stephanie J.
N1 - MDT has been supported by 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 Medical Researanch Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. APM was a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant number WT098017) and was also supported by Wellcome Trust grant WT064890. 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 grants 213506, 129680 and Academy of Finland grants 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 UK Medical Research Council (MR/K026992/1) and The Royal Society of Edinburgh. ÅJ is supported by the Swedish Society for Medical Research (SSMF), 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 grants K2007-66X-20270-01-3 and 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 network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research, and the German Asthma and COPD Network (COSYCONET) (grant no.01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, BMBF 01GI0883). ExomeChip data have been supported by the Federal Ministry of Education and Research (grant no. 03Z1CN22) and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. UKHLS is supported by grants WT098051 (Wellcome Trust) and ES/H029745/1 (Economic and Social Research Council). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. Lies Lahousse is a Postdoctoral Fellow of the Research Foundation - Flanders (FWO grant G035014N). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Scientific Research (NOW), the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Genotyping in the Rotterdam study was supported by Netherlands Organization for Scientific Research (NOW grants 175.010.2005.011 ; 911-03-305 012), the Research Institute for Diseases in the Elderly (RIDE2 grants 014-93-015) and Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA grant050-060-810). MESA/MESA SHARe is supported by HHS (HHSN268201500003I), NIH/NHLBI (contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169) and HIH/NCATS (contracts UL1-TR-000040, UL1-TR-001079, UL1-TR-001881, DK063491). MESA SHARe is funded by NIH/NHLBI contract N02-HL-64278, MESA Air is funded by US EPA (RD831697) and MESA Spirometry funded by NIH/NHLBI (R01-HL077612). SSR and BMP are supported by NIH/NHLBI grant rare variants and NHLBI traits in deeply phenotyped cohorts (R01-HL120393). Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL068986, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 and R01HL085251 from the National Institute on Aging (NIA). The provision of genotyping data was suprovidedpported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). DOMK received funding from the Dutch Science Organisation (ZonMW-VENI Grant 916.14.023). The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-François Deleuze. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. SAPALDIA was supported by the Swiss National Science Foundation (grants no 33CS30-148470/1, 33CSCO-134276/1, 33CSCO-108796, , 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPulDP3_129021/1, PMPDP3_141671/1), the Federal Office for the Environment, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton's Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais, Graubünden and Zurich, Stiftung ehemals Bündner Heilstätten, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK.. The Croatia KORCULA study was supported by the Ministry of Science, Education and Sport in the Republic of Croatia (108-1080315-0302). JD, JCL, WG and GTOC are supported by NIH/NHLBI Contract HHSN268201500001I. Genotyping, quality control and calling of the Illumina HumanExome BeadChip in the Framingham Heart Study was supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O’Donnell, Principle Investigators). The AGES study is supported by the NIH (N01-AG012100), the Iceland Parliament (Alþingi) and the Icelandic Heart Association. HABC was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106; NIA grant R01-AG028050, and NINR grant R01- NR012459 and was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The HABC genome-wide association study was funded by NIA grant 1R01AG032098- 01A1 and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. JGW is supported by U54GM115428 from the National Institute of General Medical Sciences. © 2018 Jackson VE et al.
PY - 2018/8/7
Y1 - 2018/8/7
N2 - Background: 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 (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/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.
AB - Background: 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 (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/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.
KW - Lung function
KW - respiratory
KW - exome array
KW - GWAS
KW - COPD
UR - http://www.scopus.com/inward/record.url?scp=85062156888&partnerID=8YFLogxK
U2 - 10.12688/wellcomeopenres.12583.3
DO - 10.12688/wellcomeopenres.12583.3
M3 - Article
C2 - 30175238
SN - 2398-502X
VL - 3
JO - Wellcome Open Research
JF - Wellcome Open Research
M1 - 4
ER -