Maxime Lamontagne1, Wim Timens2, Ke Hao3, Yohan Bossé4, Michel Laviolette1, Katrina Steiling5, Joshua D Campbell5, Christian Couture1, Massimo Conti1, Karen Sherwood6, James C Hogg7, Corry-Anke Brandsma2, Maarten van den Berge8, Andrew Sandford9, Stephen Lam10, Marc E Lenburg5, Avrum Spira5, Peter D Paré9, David Nickle11, Don D Sin9, Dirkje S Postma8. 1. Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada. 2. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands. 3. Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, New York, USA. 4. Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada Department of Molecular Medicine, Laval University, Québec, Canada. 5. Division of Computational Biomedicine, Bioinformatics Program, Boston University, Boston, Massachusetts, USA. 6. University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada. 7. University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 8. Department of Pulmonology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands. 9. University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 10. British Columbia Cancer Agency, Vancouver, British Columbia, Canada. 11. Merck & Co Inc, Rahway, New Jersey, USA.
Abstract
BACKGROUND: COPD is a complex chronic disease with poorly understood pathogenesis. Integrative genomic approaches have the potential to elucidate the biological networks underlying COPD and lung function. We recently combined genome-wide genotyping and gene expression in 1111 human lung specimens to map expression quantitative trait loci (eQTL). OBJECTIVE: To determine causal associations between COPD and lung function-associated single nucleotide polymorphisms (SNPs) and lung tissue gene expression changes in our lung eQTL dataset. METHODS: We evaluated causality between SNPs and gene expression for three COPD phenotypes: FEV(1)% predicted, FEV(1)/FVC and COPD as a categorical variable. Different models were assessed in the three cohorts independently and in a meta-analysis. SNPs associated with a COPD phenotype and gene expression were subjected to causal pathway modelling and manual curation. In silico analyses evaluated functional enrichment of biological pathways among newly identified causal genes. Biologically relevant causal genes were validated in two separate gene expression datasets of lung tissues and bronchial airway brushings. RESULTS: High reliability causal relations were found in SNP-mRNA-phenotype triplets for FEV(1)% predicted (n=169) and FEV(1)/FVC (n=80). Several genes of potential biological relevance for COPD were revealed. eQTL-SNPs upregulating cystatin C (CST3) and CD22 were associated with worse lung function. Signalling pathways enriched with causal genes included xenobiotic metabolism, apoptosis, protease-antiprotease and oxidant-antioxidant balance. CONCLUSIONS: By using integrative genomics and analysing the relationships of COPD phenotypes with SNPs and gene expression in lung tissue, we identified CST3 and CD22 as potential causal genes for airflow obstruction. This study also augmented the understanding of previously described COPD pathways. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND:COPD is a complex chronic disease with poorly understood pathogenesis. Integrative genomic approaches have the potential to elucidate the biological networks underlying COPD and lung function. We recently combined genome-wide genotyping and gene expression in 1111 human lung specimens to map expression quantitative trait loci (eQTL). OBJECTIVE: To determine causal associations between COPD and lung function-associated single nucleotide polymorphisms (SNPs) and lung tissue gene expression changes in our lung eQTL dataset. METHODS: We evaluated causality between SNPs and gene expression for three COPD phenotypes: FEV(1)% predicted, FEV(1)/FVC and COPD as a categorical variable. Different models were assessed in the three cohorts independently and in a meta-analysis. SNPs associated with a COPD phenotype and gene expression were subjected to causal pathway modelling and manual curation. In silico analyses evaluated functional enrichment of biological pathways among newly identified causal genes. Biologically relevant causal genes were validated in two separate gene expression datasets of lung tissues and bronchial airway brushings. RESULTS: High reliability causal relations were found in SNP-mRNA-phenotype triplets for FEV(1)% predicted (n=169) and FEV(1)/FVC (n=80). Several genes of potential biological relevance for COPD were revealed. eQTL-SNPs upregulating cystatin C (CST3) and CD22 were associated with worse lung function. Signalling pathways enriched with causal genes included xenobiotic metabolism, apoptosis, protease-antiprotease and oxidant-antioxidant balance. CONCLUSIONS: By using integrative genomics and analysing the relationships of COPD phenotypes with SNPs and gene expression in lung tissue, we identified CST3 and CD22 as potential causal genes for airflow obstruction. This study also augmented the understanding of previously described COPD pathways. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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