Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10^-49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Figure 1

Manhattan plots of genome-wide association results for FEV₁ (top), FEV₁/FVC (middle) and FVC (bottom). Previously reported signals are highlighted in dark blue (except signals with P>5x10^-4in this study); and novel signals are coloured in red. Signals are highlighted for the trait with which they showed strongest association only. The red and blue lines correspond to the genome-wide significance level (P=5x10^-8, -log₁₀P=7.3) and the threshold used to select signals for follow up in stage 2 (P=5x10^-7, -log₁₀P=6.3) respectively. Labels show the nearest gene to the novel sentinel variants. There were 2 independent novel signals near CDC7 and TGFBR3 on chromosome 1 (labelled as CDC7/TGFBR3). See Supplementary Table 3 for full results. Image was created using a modified version of the R package qqman.

Figure 2

Genetic Risk Score associations with COPD susceptibility (a) Forest plot of COPD results for the risk score analysis. Odds ratios per standard deviation of the risk score (~6 alleles) are presented for each study. Studies are grouped according to study design and phenotyping: “eMR”, electronic medical records, which used ICD codes to define COPD (DiscovEHR also used spirometry to refine the COPD definition); “case-control”, COPD case-control, which used post-bronchodilator spirometry to define COPD; “lung resection cohort”, which used a combination of pre and post-bronchodilator spirometry to define COPD; the Icelandic Biobank, deCODE, where cases were selected from a population based study and a study of COPD patients and defined using a spirometric definition, controls were selected as individuals within the cohort that were not known cases (no spirometric definition was used for controls); and UK Biobank (excluding UK BiLEVE), which used spirometry to define both COPD cases and controls. Further details are provided in the Supplementary Note. (b) Odds ratios for spirometrically-defined COPD for weighted genetic risk score deciles in UK Biobank (10,547 cases, pre-bronchodilator % predicted FEV₁<80% and FEV₁/FVC<0.7, and 53,948 controls, FEV₁/FVC>0.7 and % predicted FEV₁>80%, weights derived from non-discovery populations). For each decile, odds ratios were obtained using a logistic regression adjusted for age, age², sex, height, smoking status, pack-years and the first 10 ancestry principal components. The OR comparing the 10^th and the 1^st decile in ever-smokers only was 3.35 (95% CI 2.93 to 3.84) and in never-smokers only was 4.27 (95% CI 3.61 to 5.06).