title: Beyond GWAS in COPD: probing the landscape between gene-set associations, genome-wide associations and protein-protein interaction networks.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass., USA.
authors.forename: Merry-Lynn Noelle
authors.initials: ML
authors.lastname: McDonald
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.forename: Yang-Yu
authors.initials: YY
authors.lastname: Liu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Harshfield
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D060066:Protein Interaction Maps; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*