Integrative genomics identifies new genes associated with severe COPD and emphysema

Respir Res. 2018 Mar 22;19(1):46. doi: 10.1186/s12931-018-0744-9.


Background: Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes. Integrative methods that combine gene expression data with GWAS can provide more power in discovering disease-associated genes and give mechanistic insight into regulated genes.

Methods: We applied a recently described method that imputes gene expression using reference transcriptome data to genome-wide association studies for two phenotypes (severe COPD and quantitative emphysema) and blood and lung tissue gene expression datasets. We further tested the potential causality of individual genes using multi-variant colocalization.

Results: We identified seven genes significantly associated with severe COPD, and five genes significantly associated with quantitative emphysema in whole blood or lung. We validated results in independent transcriptome databases and confirmed colocalization signals for PSMA4, EGLN2, WNT3, DCBLD1, and LILRA3. Three of these genes were not located within previously reported GWAS loci for either phenotype. We also identified genetically driven pathways, including those related to immune regulation.

Conclusions: An integrative analysis of GWAS and gene expression identified novel associations with severe COPD and quantitative emphysema, and also suggested disease-associated genes in known COPD susceptibility loci.

Trial registration: NCT00608764 , Registry:, Date of Enrollment of First Participant: November 2007, Date Registered: January 28, 2008 (retrospectively registered); NCT00292552 , Registry:, Date of Enrollment of First Participant: December 2005, Date Registered: February 14, 2006 (retrospectively registered).

Keywords: Chronic obstructive pulmonary disease; Emphysema; Gene expression; Genome-wide association studies.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clinical Trials as Topic / methods
  • Cohort Studies
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods*
  • Genomics / methods*
  • Humans
  • Pulmonary Disease, Chronic Obstructive / diagnosis
  • Pulmonary Disease, Chronic Obstructive / epidemiology
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Emphysema / diagnosis
  • Pulmonary Emphysema / epidemiology
  • Pulmonary Emphysema / genetics*
  • Severity of Illness Index*

Associated data


Grant support