Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both the polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug repurposing opportunities that could improve lung function.

Impaired lung function is associated with significant morbidity and mortality. Restrictive and obstructive lung disorders are a large contributor to decreased lung function, as well as the acute impact of infection. Measures of pulmonary function are heritable, and thus, we sought to utilise genomics to propose novel drug repurposing candidates which could improve respiratory outcomes. Lung function measures were found to be genetically correlated with metabolic and hormone traits which could be pharmacologically modulated, with a causal effect of increased fasting glucose on diminished lung function supported by latent causal variable models and Mendelian randomisation. We developed polygenic scores for lung function specifically within pathways with known drug targets to prioritise individuals who may benefit from particular drug repurposing opportunities, accompanied by transcriptome-wide association studies to identify drug-gene interactions with potential lung function increasing modes of action. These drug repurposing candidates were further considered relative to the host-viral interactome of three viruses with associated respiratory pathology (SARS-CoV2, influenza, and human adenovirus). We uncovered an enrichment amongst glycaemic pathways of human proteins which putatively interact with virally expressed SARS-CoV2 proteins, suggesting that antihyperglycaemic agents may have a positive effect both on lung function and SARS-CoV2 progression.

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