Figure 1. Overview of strategies for genetically informed drug repurposing to improve lung function.

The left flow chart outlines our workflow for using causal inference to identify drug targets, while the right flow chart shows the workflow for functionally partitioning the heritable component into drug targets. In both cases, we utilise or integrate genome-wide association studies (GWAS) data for lung function (including three spirometry phenotypes: forced expiratory volume in 1 s [FEV₁], forced vital capacity [FVC], and their ratio [FEV₁/FVC]) and quantitative biochemical traits (e.g. hormones and metabolites) which can be pharmacologically modulated. Using this data, we established genetic correlation between lung function and the biochemical traits using linkage disequilibrium score regression (LDSC). We then constructed a latent causal variable (LCV) model to investigate evidence of causality for significantly correlated biochemical–lung function trait pairs. To further support causal inference between significant pairs, we implemented Mendelian randomisation. Where a causal relationship between a modifiable biochemical trait and lung function is established, we can infer a novel treatment. The right flow chart shows the workflow for utilising heritable components for drug repurposing. Specifically, polygenic scores for lung function were calculated using lung function GWAS single nucleotide polymorphisms (SNPs) within biological pathways that can be targeted by approved drugs, rather than a genome-wide score. Individuals with low genetically predicted lung function by a pharmagenic enrichment score (PES) (low PES) relative to a reference population may benefit from a compound which modulates said pathway. To further support putative genetically predicted targets for drug repositioning a transcriptome-wide association study of lung function was performed. Druggable genes for which genetically predicted expression was correlated with a spirometry measure. Genes with positive genetic covariance between imputed expression and lung function (i.e. increased expression associated with increased lung function) could be modulated by an agonist compound, whilst genes for which decreased predicted expression is associated with improved lung function could be targeted by an antagonist compound.

Figure 1—figure supplement 1. Diagrammatic overview of strategies for genetically informed drug repurposing to improve lung function.

The left column outlines our workflow for using causal inference to identify drug targets, while the right side shows the workflow for functionally partitioning the heritable component into drug targets. In both cases, we utilise or integrate genome-wide association studies (GWAS) data for lung function (including three spirometry phenotypes: forced expiratory volume in 1 s [FEV₁], forced vital capacity [FVC], and their ratio [FEV₁/FVC]) and quantitative biochemical traits (e.g. hormones and metabolites) which can be pharmacologically modulated. Using this data, we established genetic correlation between lung function and the biochemical traits using linkage disequilibrium score regression (LDSC) (left column). We then constructed a latent causal variable (LCV) model to investigate evidence of causality for significantly correlated biochemical–lung function trait pairs. To further support causal inference between significant pairs, we implemented Mendelian randomisation. Where a causal relationship between a modifiable biochemical trait and lung function is established, we can infer a novel treatment. The right column shows the workflow for utilising the pharmagenic enrichment score (PES) framework for precision drug repositioning. Specifically, polygenic scores for lung function were calculated using lung function GWAS SNPs within biological pathways that can be targeted by approved drugs, rather than a genome-wide score. Individuals with low genetically predicted lung function by a PES (low PES) relative to a reference population (orange shaded distribution in right panel 3) may benefit from a compound which modulates said pathway. To further support putative genetically predicted targets for drug repositioning, a transcriptome-wide association study of lung function was performed. Druggable genes for which genetically predicted expression was correlated with a spirometry measure. Genes with positive genetic covariance between imputed expression and lung function (i.e. increased expression associated with increased lung function) could be modulated by an agonist compound, whilst genes for which decreased predicted expression is associated with improved lung function could be targeted by an antagonist compound.