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Integrative pathway genomics of lung function and airflow obstruction.

TitleIntegrative pathway genomics of lung function and airflow obstruction.
Publication TypeJournal Article
Year of Publication2015
AuthorsGharib SA, Loth DW, Artigas MSoler, Birkland TP, Wilk JB, Wain LV, Brody JA, Obeidat M'en, Hancock DB, Tang W, Rawal R, H Boezen M, Imboden M, Huffman JE, Lahousse L, Alves AC, Manichaikul A, Hui J, Morrison AC, Ramasamy A, Smith A V, Gudnason V, Surakka I, Vitart V, Evans DM, Strachan DP, Deary IJ, Hofman A, Gläser S, Wilson JF, North KE, Zhao JHua, Heckbert SR, Jarvis DL, Probst-Hensch N, Schulz H, Barr GR, Jarvelin M-R, O'Connor GT, Kähönen M, Cassano PA, Hysi PG, Dupuis J, Hayward C, Psaty BM, Hall IP, Parks WC, Tobin MD
Secondary AuthorsLondon SJ
Corporate AuthorsCHARGE Consortium, SpiroMeta Consortium
JournalHum Mol Genet
Date Published2015 12 01
KeywordsAirway Obstruction, Animals, Cell Proliferation, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Immune System, Lung, Male, Metabolic Networks and Pathways, Mice, Phenotype, Polymorphism, Single Nucleotide, Signal Transduction

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.

Alternate JournalHum Mol Genet
PubMed ID26395457
PubMed Central IDPMC4643644
Grant ListETM/55 / / Chief Scientist Office / United Kingdom
CZB/4/505 / / Chief Scientist Office / United Kingdom
G1001799 / / Medical Research Council / United Kingdom
R01 HL077612 / HL / NHLBI NIH HHS / United States
G1000861 / / Medical Research Council / United Kingdom
MC_PC_12010 / / Medical Research Council / United Kingdom
MR/K026992/1 / / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
MR/N01104X/1 / / Medical Research Council / United Kingdom
MC_UU_12013/4 / / Medical Research Council / United Kingdom
MC_PC_U127561128 / / Medical Research Council / United Kingdom
G0902313 / / Medical Research Council / United Kingdom
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom