Integrative genomics identifies new genes associated with severe COPD and emphysema

• Main Authors: Phuwanat Sakornsakolpat, Jarrett D. Morrow, Peter J. Castaldi, Craig P. Hersh, Yohan Bossé, Edwin K. Silverman, Ani Manichaikul, Michael H. Cho
• Format: Article
• Language: English
• Published: BMC 2018-03-01
• Series: Respiratory Research
• Subjects: Chronic obstructive pulmonary disease; Emphysema; Genome-wide association studies; Gene expression
• Online Access: http://link.springer.com/article/10.1186/s12931-018-0744-9

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