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Integrative pathway genomics of lung function and airflow obstruction

Gharib, Sina A. ; Loth, Daan W. ; Soler Artigas, María ; Birkland, Timothy P. ; Wilk, Jemma B. ; Wain, Louise V. ; Brody, Jennifer A. ; Obeidat, Ma'en ; Hancock, Dana B. ; Tang, Wenbo ; Rawal, Rajesh ; Boezen, H. Marike ; Imboden, Medea ; Huffman, Jennifer E. ; Lahousse, Lies ; Alves, Alexessander C. ; Manichaikul, Ani ; Hui, Jennie ; Morrison, Alanna C. ; Ramasamy, Adaikalavan ; Smith, Albert Vernon ; Gudnason, Vilmundur ; Surakka, Ida ; Vitart, Veronique ; Evans, David M. ; Strachan, David P. ; Deary, Ian J. ; Hofman, Albert ; Gläser, Sven ; Wilson, James F. ; North, Kari E. ; Zhao, Jing Hua ; Heckbert, Susan R. ; Jarvis, Deborah L. ; Probst-Hensch, Nicole ; Schulz, Holger ; Barr, R. Graham ; Jarvelin, Marjo-Riitta ; O'Connor, George T. ; Kähönen, Mika ; Cassano, Patricia A. ; Hysi, Pirro G. ; Dupuis, Josée ; Hayward, Caroline ; Psaty, Bruce M. ; Hall, Ian P. ; Parks, William C. ; Tobin, Martin D. ; London, Stephanie J.

In: Human Molecular Genetics, 2015, vol. 24, no. 23, p. 6836-6848

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    Titre
    • Integrative pathway genomics of lung function and airflow obstruction
    Auteur
    • Gharib, Sina A.. Computational Medicine Core, Center for Lung Biology
    • Loth, Daan W.. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
    • Soler Artigas, María. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
    • Birkland, Timothy P.. Computational Medicine Core, Center for Lung Biology
    • Wilk, Jemma B.. Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, MA, USA
    • Wain, Louise V.. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
    • Brody, Jennifer A.. Cardiovascular Health Research Unit
    • Obeidat, Ma'en. University of British Columbia, Centre for Heart Lung Innovation, Vancouver, BC, Canada
    • Hancock, Dana B.. Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, Research Triangle Institute (RTI) International, Research Triangle Park, NC, USA
    • Tang, Wenbo. Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
    • Rawal, Rajesh. Institute of Genetic Epidemiology
    • Boezen, H. Marike. Department of Epidemiology
    • Imboden, Medea. Swiss Tropical and Public Health Institute, Basel, Switzerland
    • Huffman, Jennifer E.. MRC Human Genetics Unit, MRC IGMM
    • Lahousse, Lies. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
    • Alves, Alexessander C.. School of Public Health
    • Manichaikul, Ani. Center for Public Health Genomics
    • Hui, Jennie. PathWest Laboratory Medicine WA, Nedlands, Australia
    • Morrison, Alanna C.. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
    • Ramasamy, Adaikalavan. Department of Medical and Molecular Genetics
    • Smith, Albert Vernon. Iceland Heart Association, Kopavogur, Iceland
    • Gudnason, Vilmundur. Iceland Heart Association, Kopavogur, Iceland
    • Surakka, Ida. Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland
    • Vitart, Veronique. MRC Human Genetics Unit, MRC IGMM
    • Evans, David M.. University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent St Woolloongabba, QLD 4102, Australia
    • Strachan, David P.. Population Health Research Institute, St George's, University of London, London, UK
    • Deary, Ian J.. Centre for Cognitive Ageing and Cognitive Epidemiology
    • Hofman, Albert. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
    • Gläser, Sven. Department of Internal Medicine B, Pneumology, Cardiology, Intensive Care and Infectious Diseases, University Hospital Greifswald, Greifswald, Germany
    • Wilson, James F.. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, Scotland, UK
    • North, Kari E.. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    • Zhao, Jing Hua. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
    • Heckbert, Susan R.. Cardiovascular Health Research Unit
    • Jarvis, Deborah L.. Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute
    • Probst-Hensch, Nicole. Swiss Tropical and Public Health Institute, Basel, Switzerland
    • Schulz, Holger. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
    • Barr, R. Graham. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
    • Jarvelin, Marjo-Riitta. Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
    • O'Connor, George T.. Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
    • Kähönen, Mika. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland
    • Cassano, Patricia A.. Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
    • Hysi, Pirro G.. Department of Twins Research and Genetic Epidemiology, King's College, London, UK
    • Dupuis, Josée. The NHLBI's Framingham Heart Study, Framingham, MA, USA
    • Hayward, Caroline. MRC Human Genetics Unit, MRC IGMM
    • Psaty, Bruce M.. Department of Medicine
    • Hall, Ian P.. Division of Respiratory Medicine, University Hospital of Nottingham, Nottingham, UK
    • Parks, William C.. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA and
    • Tobin, Martin D.. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
    • London, Stephanie J.. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institute of Health, Department of Health and Human Services, Research Triangle Park, NC, USA
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • Human Molecular Genetics, 2015, vol. 24, no. 23, p. 6836-6848. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:303984
    Summary
    Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease