Supplementary Material for: Beyond GWAS in COPD: Probing the Landscape between Gene-Set Associations, Genome-Wide Associations and Protein-Protein Interaction Networks
McDonald M.-L.N.
Mattheisen M.
Cho M.H.
Liu Y.-Y.
Harshfield B.
Hersh C.P.
Bakke P.
Gulsvik A.
Lange C.
Beaty T.H.
10.6084/m9.figshare.5126857.v1
https://karger.figshare.com/articles/dataset/Supplementary_Material_for_Beyond_GWAS_in_COPD_Probing_the_Landscape_between_Gene-Set_Associations_Genome-Wide_Associations_and_Protein-Protein_Interaction_Networks/5126857
<b><i>Objectives:</i></b> To use a systems biology approach to integrate genotype and protein-protein interaction (PPI) data to identify disease network modules associated with chronic obstructive pulmonary disease (COPD) and to perform traditional pathway analysis. <b><i>Methods:</i></b> We utilized a standard gene-set association approach (FORGE) using gene-based association analysis and gene-set definitions from the molecular signatures database (MSigDB). As a discovery step, we analyzed GWAS results from 2 well-characterized COPD cohorts: COPDGene and GenKOLS. We used a third well-characterized COPD case-control cohort for replication: ECLIPSE. Next, we used dmGWAS, a method that integrates GWAS results with PPI, to identify COPD disease modules. <b><i>Results:</i></b> No gene-sets reached experiment-wide significance in either discovery population. We identified a consensus network of 10 genes identified in modules by integrating GWAS results with PPI that replicated in COPDGene, GenKOLS, and ECLIPSE. Members of 4 gene-sets were enriched among these 10 genes: (i) lung adenocarcinoma tumor-sequencing genes, (ii) IL-7 pathway genes, (iii) kidney cell response to arsenic, and (iv) CD4 T-cell responses. Further, several genes have also been associated with pathophysiology relevant to COPD including <i>KCNK3</i>, <i>NEDD4L</i>, and <i>RIN3</i>. In particular, <i>KCNK3</i> has been associated with pulmonary arterial hypertension, a common complication in advanced COPD. <b><i>Conclusion:</i></b> We report a set of new genes that may influence the etiology of COPD that would not have been identified using traditional GWAS and pathway analyses alone.
2014-08-27 00:00:00
COPD
Genome-wide scan
Protein-protein interaction network
Gene-set association
Pathway association
Disease module