New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Figure 1:. Study design

Tier 1 signals had P<5×10⁻⁹ in UK Biobank and P<10⁻³ in SpiroMeta with consistent direction of effect. Tier 2 signals had P<5×10⁻⁹ in the meta-analysis of UK Biobank and SpiroMeta with P<10⁻³ in UK Biobank and P<10⁻³ in SpiroMeta with consistent directions of effect. Signals with P<5×10⁻⁹ in the meta-analysis of UK Biobank and SpiroMeta, and that had consistent directions of effect but did not meet P<10⁻³ in both cohorts were reported as Tier 3.

Figure 2:. Strength and direction of association across four lung function traits for 139 novel signals:

Signals are in chromosome and genomic position order from top to bottom then left to right. Red indicates a decrease in the lung function trait; blue indicates an increase. All effects are aligned to the allele associated with decreased FEV₁/FVC, hence the FEV₁/FVC column is only red or white. P-values are from the meta-analysis of UK Biobank and SpiroMeta (n=400,102). The scale points are thresholds used for (i) confirmation in 2-stage analysis and 1-stage analysis (P<10⁻³); (ii) confirmation of association of previous signals (P<10⁻⁵); (iii) signal selection in 2-stage and 1-stage analysis (P<5×10⁻⁹); capped at (P<10⁻²⁰). FEV_1, forced expired volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow

Figure 3:. Association of weighted genetic risk score (wGRS) with COPD and FEV₁/FVC.

a. Association of the wGRS with FEV₁/FVC and COPD in UK Biobank (UKB) and China Kadoorie Biobank (CKB) (Supplementary Table 19). Left-hand axis: standard deviation (SD) change in FEV₁/FVC per SD increase in wGRS (light grey bars, N=total sample size). Right-hand axis: the translation of this effect to COPD (GOLD stage 2–4) odds ratio (OR) per SD increase in wGRS in the same individuals for UKB ancestries with >100 COPD cases (dark grey bars, N=number of cases + number of controls. Whiskers represent 95% confidence intervals. Some variants in the wGRS were discovered in UKB Europeans, therefore UKB Europeans are shown for reference only (far left, ‘Discovery sample’). All other ancestral groups are independent to UKB Europeans. b. OR for COPD per SD increase in wGRS in six study groups. COPD was defined using GOLD 2–4 criteria (Supplementary Table 21: means and SDs of risk scores). The vertical black line indicates the null effect (OR=1). The point estimate of each study is represented by a box proportional to study weight; whiskers represent 95% confidence intervals. The diamond represents a fixed effect meta-analysis of the five European-ancestry groups, the width of which represents the 95% confidence interval (I² statistic=0). c. OR for COPD according to deciles of the wGRS, with decile 1 (the 10% of individuals with the lowest GRS) as the reference group. Each point represents a meta-analysis of results for a given comparison (e.g. decile 2 vs reference, decile 3 vs reference, etc.) in five external European-ancestry study groups (COPDGene, ECLIPSE, GenKOLS, SPIROMICS, NETT-NAS). Deciles were calculated and models were run in each group separately. Error bars show 95% confidence intervals (Supplementary Table 22).

Figure 4:. Individual PheWAS with 279 variants (traits passing FDR 1% threshold)

Separate association of 279 variants with 2,411 traits (FDR<1%) in UK Biobank (n up to 379,337). In each category, the trait with the strongest association, i.e. highest –log₁₀(FDR), is shown first, followed by other traits in that category in descending order of –log₁₀(FDR). Categories are colour-coded, and outcomes are denoted with a circular or triangular point, according to whether they were coded as binary or quantitative. The top association per-category is labelled with its rsID number, and a plain English label describing the trait. The letter at the beginning of each label allows easy cross-reference with the categories labelled in the legend. Zoomed in versions of each category with visible trait names and directionality are available in Supplementary Figure 10. These plots have signed log₁₀(FDR) values, where a positive values indicates that a positive SNP-trait association is concordant with the risk allele for reduced lung function (as measured by lower FEV₁/FVC). Tabulated results of all SNP-trait PheWAS associations associated at an FDR of<1% are available in Supplementary Table 23.

Figure 5:. PheWAS with genetic risk score (traits passing FDR 1% threshold)

Association of 279 variant weighted genetic risk score with 2,453 traits (FDR<1%) in UK Biobank (n up to 379,337). In each panel, the category with the strongest association, i.e. highest –log₁₀(FDR), is shown first, followed by all other associations in that category, ordered by descending order of –log₁₀(FDR). Sample sizes varied across traits and are available in Supplementary Table 25, along with the full summary statistics for each association, plus details of categorisation and plain English labels for each trait. Trait categories are colour coded, and outcomes are denoted with a circular or triangular point, according to whether they were coded as binary or quantitative. The sign of the log₁₀(FDR) value is positive where an increase in the risk score (i.e. greater risk of COPD, reduced lung function) is associated with a positive effect estimate for that trait. *QC refers to spirometry passing ERS/ATS criteria. SR=self-report; HES=Hospital Episode Statistics. a. Associations with respiratory traits. b.Associations with all other traits. ENT=Ear, Nose and Throat; FBC=Full Blood Count.