Dataset Information

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

ABSTRACT: 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 (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.

SUBMITTER: Jackson VE

PROVIDER: S-EPMC6081985 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Jackson Victoria E VE Latourelle Jeanne C JC Wain Louise V LV Smith Albert V AV Grove Megan L ML Bartz Traci M TM Obeidat Ma'en M Province Michael A MA Gao Wei W Qaiser Beenish B Porteous David J DJ Cassano Patricia A PA Ahluwalia Tarunveer S TS Grarup Niels N Li Jin J Altmaier Elisabeth E Marten Jonathan J Harris Sarah E SE Manichaikul Ani A Pottinger Tess D TD Li-Gao Ruifang R Lind-Thomsen Allan A Mahajan Anubha A Lahousse Lies L Imboden Medea M Teumer Alexander A Prins Bram B Lyytikäinen Leo-Pekka LP Eiriksdottir Gudny G Franceschini Nora N Sitlani Colleen M CM Brody Jennifer A JA Bossé Yohan Y Timens Wim W Kraja Aldi A Loukola Anu A Tang Wenbo W Liu Yongmei Y Bork-Jensen Jette J Justesen Johanne M JM Linneberg Allan A Lange Leslie A LA Rawal Rajesh R Karrasch Stefan S Huffman Jennifer E JE Smith Blair H BH Davies Gail G Burkart Kristin M KM Mychaleckyj Josyf C JC Bonten Tobias N TN Enroth Stefan S Lind Lars L Brusselle Guy G GG Kumar Ashish A Stubbe Beate B Kähönen Mika M Wyss Annah B AB Psaty Bruce M BM Heckbert Susan R SR Hao Ke K Rantanen Taina T Kritchevsky Stephen B SB Lohman Kurt K Skaaby Tea T Pisinger Charlotta C Hansen Torben T Schulz Holger H Polasek Ozren O Campbell Archie A Starr John M JM Rich Stephen S SS Mook-Kanamori Dennis O DO Johansson Åsa Å Ingelsson Erik E Uitterlinden André G AG Weiss Stefan S Raitakari Olli T OT Gudnason Vilmundur V North Kari E KE Gharib Sina A SA Sin Don D DD Taylor Kent D KD O'Connor George T GT Kaprio Jaakko J Harris Tamara B TB Pederson Oluf O Vestergaard Henrik H Wilson James G JG Strauch Konstantin K Hayward Caroline C Kerr Shona S Deary Ian J IJ Barr R Graham RG de Mutsert Renée R Gyllensten Ulf U Morris Andrew P AP Ikram M Arfan MA Probst-Hensch Nicole N Gläser Sven S Zeggini Eleftheria E Lehtimäki Terho T Strachan David P DP Dupuis Josée J Morrison Alanna C AC Hall Ian P IP Tobin Martin D MD London Stephanie J SJ

Wellcome open research 20180112

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 (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 ...[more]

PMID: 30175238

Similar Datasets

Project description:BackgroundSarcoidosis is an inflammatory disease characterized by non-caseating granuloma formation in various organs, with several recognized genetic and environmental risk factors. Despite substantial progress, the genetic determinants associated with its prognosis remain largely unknown.ObjectivesThis study aimed to identify the genetic changes involved in sarcoidosis and evaluate their clinical relevance.MethodsWe performed whole-exome sequencing (WES) in 116 sporadic sarcoidosis patients (acute sarcoidosis patients, n=58; chronic sarcoidosis patients, n=58). In addition, 208 healthy controls were selected from 1000 G East Asian population data. To identify genes enriched in sarcoidosis, Fisher exact tests were performed. The identified genes were included for further pathway analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we used the STRING database to construct a protein network of rare variants and Cytoscape to identify hub genes of signaling pathways.ResultsWES and Fisher's exact test identified 1,311 variants in 439 protein-coding genes. A total of 135 single nucleotide polymorphisms (SNPs) on 30 protein-coding genes involved in the immunological process based on the GO and KEGG enrichment analysis. Pathway enrichment analysis showed osteoclast differentiation and cytokine-cytokine receptor interactions. Three missense mutations (rs76740888, rs149664918, and rs78251590) in two genes (PRSS3 and CNN2) of immune-related genes showed significantly different mutation frequencies between the disease group and healthy controls. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis of the clinical features and mutation loci showed that the missense variant (rs76740888, Chr9:33796673 G>A) of PRSS3 [p=0.04, odds ratio (OR) = 2.49] was significantly associated with chronic disease prognosis. Additionally, the top two hub genes were CCL4 and CXCR4 based on protein-protein interaction (PPI) network analysis.ConclusionOur study provides new insights into the molecular pathogenesis of sarcoidosis and identifies novel genetic alterations in this disease, especially PRSS3, which may be promising targets for future therapeutic strategies for chronic sarcoidosis.

Dataset Information

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Publications

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets