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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.

Authors

Sina A. Gharib

Daan W. Loth

María Soler Artigas

Timothy P. Birkland

Jemma B. Wilk

Louise V. Wain

Jennifer A. Brody

Ma'en Obeidat

Dana B. Hancock

Wenbo Tang

Rajesh Rawal

H. Marike Boezen

Medea Imboden

Jennifer E. Huffman

Lies Lahousse

Alexessander C. Alves

Ani Manichaikul

Jennie Hui

Alanna C. Morrison

Adaikalavan Ramasamy

Albert Vernon Smith

Vilmundur Gudnason

Ida Surakka

Veronique Vitart

David M. Evans

David P. Strachan

Ian J. Deary

Albert Hofman

Sven Gläser

James F. Wilson

Kari E. North

Jing Hua Zhao

Susan R. Heckbert

Deborah L. Jarvis

Nicole Probst-Hensch

Holger Schulz

R. Graham Barr

Marjo-Riitta Jarvelin

George T. O'Connor

Mika Kähönen

Patricia A. Cassano

Pirro G. Hysi

Josée Dupuis

Caroline Hayward

Bruce M. Psaty

IAN HALL ian.hall@nottingham.ac.uk
Professor of Molecular Medicine

William C. Parks

Martin D. Tobin

Stephanie J. London



Abstract

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 signalling, 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-analysed 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 unravelled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

Journal Article Type Article
Publication Date Dec 1, 2015
Journal Human Molecular Genetics
Print ISSN 0964-6906
Electronic ISSN 1460-2083
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 24
Issue 23
Pages 6836-6848
APA6 Citation Gharib, S. A., Loth, D. W., Soler Artigas, M., Birkland, T. P., Wilk, J. B., Wain, L. V., …London, S. J. (2015). Integrative pathway genomics of lung function and airflow obstruction. Human Molecular Genetics, 24(23), 6836-6848. https://doi.org/10.1093/hmg/ddv378
DOI https://doi.org/10.1093/hmg/ddv378
Publisher URL https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv378
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This article has been accepted for publication in Human Molecular Genetics, Published by Oxford University Press.
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