Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Abstract

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10^-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

Figure 1. Study design

COPD, chronic obstructive pulmonary disease; FEV₁, force expiratory volume in one second; FVC, forced vital capacity. ARIC, Atherosclerosis Risk in Communities.

Figure 2. Manhattan plot

P-values are two-sided based on Wald statistics (35,735 cases and 222,076 controls) without multiple comparison adjustment. Loci are labeled with the closest gene to the lead variant.

Figure 3. Identification of target genes

(a) Overview of datasets used to identify target genes at genome-wide significant loci (b) Regional association plots at ADAMTSL3 locus showing GWAS (top), chromatin interaction in lung tissue (middle) and expression quantitative trait loci (bottom). GWAS P-values are two-sided based on Wald statistics (35,735 cases and 222,076 controls). Expression quantitative trait loci (eQTL) P-values are two-sided based on t statistics (1,038 samples). P-values for Hi-C data were calculated using binomial distribution from spline-fitted and outlier-filtered distribution of contacts. All P-values were not adjusted for multiple comparison. GREx, gene-based association using gene expression; mQTL, colocalization with methylation quantitative trait loci; Cod., significant single variant or gene-based association tests for deleterious coding variants from exome data; Hi-C, significant chromatin interaction identified in human lung or the IMR90 cell line; DHS, overlap with DNase hypersensitivity sites; GSet, prioritized genes from DEPICT.

Figure 4. Effects on COPD-related and other phenotypes

(a) Heatmap of scaled computed tomography (CT) quantitative imaging associations with the 34 genome-wide significant variants (known and replicated novel associations) with at least nominal (P < 0.05) association with any CT imaging feature in COPDGene non-Hispanic white participants. Cluster 1 variants are more associated with airway imaging features and Cluster 2 variants are more associated with emphysema imaging features. Variants are referred to by the closest gene. (b) Overlap of genome-wide significant loci of COPD and select traits from GWAS Catalog (c) Genome-wide overlapping results between COPD with pulmonary fibrosis (left) and asthma (right). PRM emphysema, emphysema quantified by parametric response mapping; UL, upper lobe of the lung; LL, lower lobe of the lung; Pi10, airway wall thickness calculated from regressing the square root of the airway wall area with the airway internal perimeter. CAD, coronary artery disease; BMD, bone mineral density.