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Integrative pathway genomics of lung function and airflow obstruction.

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posted on 06.11.2015, 11:32 by S. A. Gharib, D. W. Loth, María Soler Artigas, T. P. Birkland, J. B. Wilk, Louise V. Wain, J. A. Brody, M. Obeidat, D. B. Hancock, W. Tang, R. Rawal, H. M. Boezen, M. Imboden, J. E. Huffman, L. Lahousse, A. C. Alves, A. Manichaikul, J. Hui, A. C. Morrison, A. Ramasamy, A. V. Smith, V. Gudnason, I. Surakka, V. Vitart, D. M. Evans, D. P. Strachan, I. J. Deary, A. Hofman, S. Gläser, J. F. Wilson, K. E. North, J. H. Zhao, S. R. Heckbert, D. L. Jarvis, N. Probst-Hensch, H. Schulz, R. G. Barr, M. R. Jarvelin, G. T. O'Connor, M. Kähönen, P. A. Cassano, P. G. Hysi, J. Dupuis, C. Hayward, B. M. Psaty, I. P. Hall, W. C. Parks, Martin D. Tobin, S. J. London, CHARGE Consortium; SpiroMeta Consortium
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.

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Citation

Human Molecular Genetics, 2015, 24 (23) : 6836-6848

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Health Sciences

Version

AM (Accepted Manuscript)

Published in

Human Molecular Genetics

Publisher

Oxford University Press

issn

0964-6906

eissn

1460-2083

Acceptance date

10/09/2015

Copyright date

2015

Available date

22/09/2016

Publisher version

http://hmg.oxfordjournals.org/content/24/23/6836

Notes

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Hum. Mol. Genet. (2015) 24 (23): 6836-6848.doi: 10.1093/hmg/ddv378 is available online at: http://hmg.oxfordjournals.org/content/24/23/6836

Language

en

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