Beyond GWAS in COPD: Probing the landscape between gene-set associations, genome-wide associations and protein-protein interaction networks

Objectives: 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. Methods: 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. Results: 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 KCNK3, NEDD4L, and RIN3. In particular, KCNK3 has been associated with pulmonary arterial hypertension, a common complication in advanced COPD. Conclusion: 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.