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Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (?6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10-49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

SUBMITTER: Wain LV

PROVIDER: S-EPMC5326681 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.

Wain Louise V LV Shrine Nick N Artigas María Soler MS Erzurumluoglu A Mesut AM Noyvert Boris B Bossini-Castillo Lara L Obeidat Ma'en M Henry Amanda P AP Portelli Michael A MA Hall Robert J RJ Billington Charlotte K CK Rimington Tracy L TL Fenech Anthony G AG John Catherine C Blake Tineka T Jackson Victoria E VE Allen Richard J RJ Prins Bram P BP Campbell Archie A Porteous David J DJ Jarvelin Marjo-Riitta MR Wielscher Matthias M James Alan L AL Hui Jennie J Wareham Nicholas J NJ Zhao Jing Hua JH Wilson James F JF Joshi Peter K PK Stubbe Beate B Rawal Rajesh R Schulz Holger H Imboden Medea M Probst-Hensch Nicole M NM Karrasch Stefan S Gieger Christian C Deary Ian J IJ Harris Sarah E SE Marten Jonathan J Rudan Igor I Enroth Stefan S Gyllensten Ulf U Kerr Shona M SM Polasek Ozren O Kähönen Mika M Surakka Ida I Vitart Veronique V Hayward Caroline C Lehtimäki Terho T Raitakari Olli T OT Evans David M DM Henderson A John AJ Pennell Craig E CE Wang Carol A CA Sly Peter D PD Wan Emily S ES Busch Robert R Hobbs Brian D BD Litonjua Augusto A AA Sparrow David W DW Gulsvik Amund A Bakke Per S PS Crapo James D JD Beaty Terri H TH Hansel Nadia N NN Mathias Rasika A RA Ruczinski Ingo I Barnes Kathleen C KC Bossé Yohan Y Joubert Philippe P van den Berge Maarten M Brandsma Corry-Anke CA Paré Peter D PD Sin Don D DD Nickle David C DC Hao Ke K Gottesman Omri O Dewey Frederick E FE Bruse Shannon E SE Carey David J DJ Kirchner H Lester HL Jonsson Stefan S Thorleifsson Gudmar G Jonsdottir Ingileif I Gislason Thorarinn T Stefansson Kari K Schurmann Claudia C Nadkarni Girish G Bottinger Erwin P EP Loos Ruth J F RJ Walters Robin G RG Chen Zhengming Z Millwood Iona Y IY Vaucher Julien J Kurmi Om P OP Li Liming L Hansell Anna L AL Brightling Chris C Zeggini Eleftheria E Cho Michael H MH Silverman Edwin K EK Sayers Ian I Trynka Gosia G Morris Andrew P AP Strachan David P DP Hall Ian P IP Tobin Martin D MD

Nature genetics 20170206 3

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alle ...[more]

PMID: 28166213

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Project description:Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; smoking is the main risk factor for COPD, but genetic factors are also relevant contributors. Genome-wide association studies (GWAS) of the lung function measures used in the diagnosis of COPD have identified a number of loci, however association signals are often broad and collectively these loci only explain a small proportion of the heritability. In order to examine the association with COPD risk of genetic variants down to low allele frequencies, to aid fine-mapping of association signals and to explain more of the missing heritability, we undertook a targeted sequencing study in 300 COPD cases and 300 smoking controls for 26 loci previously reported to be associated with lung function. We used a pooled sequencing approach, with 12 pools of 25 individuals each, enabling high depth (30x) coverage per sample to be achieved. This pooled design maximised sample size and therefore power, but led to challenges during variant-calling since sequencing error rates and minor allele frequencies for rare variants can be very similar. For this reason we employed a rigorous quality control pipeline for variant detection which included the use of 3 independent calling algorithms. In order to avoid false positive associations we also developed tests to detect variants with potential batch effects and removed them before undertaking association testing. We tested for the effects of single variants and the combined effect of rare variants within a locus. We followed up the top signals with data available (only 67% of collapsing methods signals) in 4,249 COPD cases and 11,916 smoking controls from UK Biobank. We provide suggestive evidence for the combined effect of rare variants on COPD risk in TNXB and in sliding windows within MECOM and upstream of HHIP. These findings can lead to an improved understanding of the molecular pathways involved in the development of COPD.

Project description:Introduction: Chronic obstructive pulmonary disease (COPD) is an independent risk factor of non-small cell lung cancer (NSCLC). This study aimed to analyze the key genes and potential molecular mechanisms that are involved in the development from COPD to NSCLC. Methods: Expression profiles of COPD and NSCLC in GSE106899, GSE12472, and GSE12428 were downloaded from the Gene Expression Omnibus (GEO) database, followed by identification of the differentially expressed genes (DEGs) between COPD and NSCLC. Based on the identified DEGs, functional pathway enrichment and lung carcinogenesis-related networks analyses were performed and further visualized with Cytoscape software. Then, principal component analysis (PCA), cluster analysis, and support vector machines (SVM) verified the ability of the top modular genes to distinguish COPD from NSCLC. Additionally, the corrections between these key genes and clinical staging of NSCLC were studied using the UALCAN and HPA websites. Finally, a prognostic risk model was constructed based on multivariate Cox regression analysis. Kaplan-Meier survival curves of the top modular genes on the training and verification sets were generated. Results: A total of 2350, 1914, and 1850 DEGs were obtained from GSE106899, GSE12472, and GSE12428 datasets, respectively. Following analysis of protein-protein interaction networks, the identified modular gene signatures containing H2AFX, MCM2, MCM3, MCM7, POLD1, and RPA1 were identified as markers for discrimination between COPD and NSCLC. The modular gene signatures were mainly enriched in the processes of DNA replication, cell cycle, mismatch repair, and others. Besides, the expression levels of these genes were significantly higher in NSCLC than in COPD, which was further verified by the immunohistochemistry. In addition, the high expression levels of H2AFX, MCM2, MCM7, and POLD1 correlate with poor prognosis of lung adenocarcinoma (LUAD). The Cox regression prognostic risk model showed the similar results and the predictive ability of this model is independent of other clinical variables. Conclusions: This study revealed several key modules that closely relate to NSCLC with underlying disease COPD, which provide a deeper understanding of the potential mechanisms underlying the malignant development from COPD to NSCLC. This study provides valuable prognostic factors in high-risk lung cancer patients with COPD.

Project description:BACKGROUND:The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. METHODS:We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5?×?10(-7) in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5?×?10(-8)). FINDINGS:Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38?×?10(-14)), FAM13A (p=1·12?×?10(-14)), and HHIP (p=1·57?×?10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25?×?10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4?×?10(-9)). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6?×?10(-9)) and TGFB2 (overall joint meta-analysis p=8·3?×?10(-9)). INTERPRETATION:We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in ?-1 antitrypsin increase the risk of COPD. FUNDING:US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.

Dataset Information

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.

Publications

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.

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