Journal
LANCET RESPIRATORY MEDICINE
Volume 3, Issue 10, Pages 782-795Publisher
ELSEVIER SCI LTD
DOI: 10.1016/S2213-2600(15)00380-X
Keywords
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Categories
Funding
- Wellcome Trust
- European Community's Seventh Framework Programme (FP7)
- National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- NIHR
- Medical Research Council Senior Clinical Fellowship [G0902313]
- Great Wine Estates of the Margaret River region of Western Australia
- Academy of Finland, Center of Excellence in Complex Disease Genetics and SALVE [NFBC1966, 104781, 120315, 129269, 1114194]
- University Hospital Oulu
- Biocenter
- University of Oulu, Finland [75617]
- European Commission (EURO-BLCS, Framework 5 award) [QLG1-CT-2000-01643]
- NHLBI through the STAMPEED programme [5R01HL087679-02, 1RL1MH083268-01]
- NIH/NIMH [5R01MH63706:02]
- ENGAGE project [HEALTH-F4-2007-201413]
- Medical Research Council, UK (PrevMetSyn/SALVE) [G0500539, G0600705]
- EU Framework Programme 7 small-scale focused research collaborative project EurHEALTHAgeing [277849]
- Academy of Finland [213506, 129680, 265240, 263278]
- Michael Smith Foundation for Health Research (MSFHR)
- Canadian Institute for Health Research (CIHR) Integrated and Mentored Pulmonary and Cardiovascular Training programme (IMPACT)
- Wellcome Trust Sanger Institute
- European Commission: ENGAGE-European Network for Genetic
- Genomic Epidemiology
- Chief Scientist Office of the Scottish Executive
- Royal Society
- MRC [G0902313]
- HealthWay, Western Australia
- EU FP6
- Ministry of Science, Education, and Sport of the Republic of Croatia
- European Union framework program 6 EUROSPAN project
- Academy of Finland
- University Hospital Oulu, Biocenter, University of Oulu, Finland
- European Commission, EURO-BLCS Framework 5 award
- NHLBI grant through the STAMPEED programme
- NIH/NIMH
- European Commission, ENGAGE project
- Medical Research Council, UK, PrevMetSyn/SALVE
- European Commission, EU Framework Programme 7 small-scale focused research collaborative project EurHEALTHAgeing
- Intramural Research Program of the NIH, National Institute of Environmental Health Sciences
- Coordination of the ECRHS-phenotype acquisition, EU
- Gabriel project-genotyping, EU
- Medical Research Fund of the Tampere University Hospital
- Chaire de pneumologie de la Fondation JD Begin de l'Universite Laval
- Fondation de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec
- Respiratory Health Network of the FRQS
- Canadian Institutes of Health Research [MOP - 123369]
- Cancer Research Society and Read for the Cure
- Fonds de recherche Quebec - Sante (FRQS)
- Medical Research Council [G0000934]
- Wellcome Trust [068545/Z/02, 076113/B/04/Z, 079895]
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Allergy and Infectious Diseases
- National Human Genome Research Institute
- National Institute of Child Health and Human Development
- Juvenile Diabetes Research Foundation International
- National Institute for Health Research Cambridge Biomedical Research Centre
- European Commission Framework Programme 6 [018996]
- French Ministry of Research
- National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C]
- National Institutes of Health
- NIH Roadmap for Medical Research
- [U01 DK062418]
- [UL1RR025005]
- Chief Scientist Office [CZB/4/710] Funding Source: researchfish
- Medical Research Council [G0902313, MC_PC_U127561128, G0000934, MC_PC_12010, MR/N01104X/1, G1000861, G1001799, G0600705] Funding Source: researchfish
- MRC [MR/N01104X/1, G0000934, MC_PC_12010, G0600705, G0902313, G1001799, G1000861, MC_PC_U127561128] Funding Source: UKRI
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Background Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. Methods The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. Findings SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. Interpretation The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico.
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