Abstract
BackgroundGenome-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.MethodsWe 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.ResultsWe 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.ConclusionsAn 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 registrationNCT00608764, 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).
Highlights
Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema
Severe COPD We first examined the association between severe COPD and imputed gene expression
Significant associations based on gene-based Bonferroni corrections for DGNBlood and Genotype Tissue Expression (GTEx)-Lung are shown in Table 3 and Fig. 2
Summary
Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. While most GWAS studies do not concomitantly measure gene expression, the strong relationship of genetic variation to gene expression allows one to use gene expression reference datasets to predict gene expression given a set of genotypes, and subsequently identify gene expression differences for a given phenotype. This approach has been implemented in software called S-PrediXcan and TWAS [8,9,10]. Aggregating information from variant level to infer genelevel associations increases the power to discover more genes at loci not previously implicated by GWAS and gives mechanistic insight regarding genes being regulated via disease-associated genetic variants [7, 11]
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