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Integrative pathway genomics of lung function and airflow obstruction

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, et al.
(2015) HUMAN MOLECULAR GENETICS. 24(23). p.6836-6848
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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 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.
Keywords
EXPRESSION, METAANALYSIS, GENOMEWIDE ASSOCIATION, MATRIX METALLOPROTEINASES, PULMONARY-DISEASE, SET ENRICHMENT ANALYSIS, WIDE ASSOCIATION, INFLAMMATION, IDENTIFICATION, RISK

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Citation

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Chicago
Gharib, Sina A, Daan W Loth, María Soler Artigas, Timothy P Birkland, Jemma B Wilk, Louise V Wain, Jennifer A Brody, et al. 2015. “Integrative Pathway Genomics of Lung Function and Airflow Obstruction.” Human Molecular Genetics 24 (23): 6836–6848.
APA
Gharib, S. A., Loth, D. W., Artigas, M. S., Birkland, T. P., Wilk, J. B., Wain, L. V., Brody, J. A., et al. (2015). Integrative pathway genomics of lung function and airflow obstruction. HUMAN MOLECULAR GENETICS, 24(23), 6836–6848.
Vancouver
1.
Gharib SA, Loth DW, Artigas MS, Birkland TP, Wilk JB, Wain LV, et al. Integrative pathway genomics of lung function and airflow obstruction. HUMAN MOLECULAR GENETICS. 2015;24(23):6836–48.
MLA
Gharib, Sina A, Daan W Loth, María Soler Artigas, et al. “Integrative Pathway Genomics of Lung Function and Airflow Obstruction.” HUMAN MOLECULAR GENETICS 24.23 (2015): 6836–6848. Print.
@article{7098983,
  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 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.},
  author       = {Gharib, Sina A and Loth, Daan W and Artigas, Mar{\'i}a Soler and Birkland, Timothy P and Wilk, Jemma B and Wain, Louise V and Brody, Jennifer A and Obeidat, Ma'en and Hancock, Dana B and Tang, Wenbo and Rawal, Rajesh and Boezen, H Marike and Imboden, Medea and Huffman, Jennifer E and Lahousse, Lies and Alves, Alexessander C and Manichaikul, Ani and Hui, Jennie and Morrison, Alanna C and Ramasamy, Adaikalavan and Smith, Albert Vernon and Gudnason, Vilmundur and Surakka, Ida and Vitart, Veronique and Evans, David M and Strachan, David P and Deary, Ian J and Hofman, Albert and Gl{\"a}ser, Sven and Wilson, James F and North, Kari E and Zhao, Jing Hua and Heckbert, Susan R and Jarvis, Deborah L and Probst-Hensch, Nicole and Schulz, Holger and Barr, R Graham and Jarvelin, Marjo-Riitta and O'Connor, George T and K{\"a}h{\"o}nen, Mika and Cassano, Patricia A and Hysi, Pirro G and Dupuis, Jos{\'e}e and Hayward, Caroline and Psaty, Bruce M and Hall, Ian P and Parks, William C and Tobin, Martin D and London, Stephanie J},
  issn         = {0964-6906},
  journal      = {HUMAN MOLECULAR GENETICS},
  keyword      = {EXPRESSION,METAANALYSIS,GENOMEWIDE ASSOCIATION,MATRIX METALLOPROTEINASES,PULMONARY-DISEASE,SET ENRICHMENT ANALYSIS,WIDE ASSOCIATION,INFLAMMATION,IDENTIFICATION,RISK},
  language     = {eng},
  number       = {23},
  pages        = {6836--6848},
  title        = {Integrative pathway genomics of lung function and airflow obstruction},
  url          = {http://dx.doi.org/10.1093/hmg/ddv378},
  volume       = {24},
  year         = {2015},
}
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