Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function.

William R Reay,John R Attia,Rodney J Scott,Sahar I El Shair,Mark A Mcevoy,Carlos Riveros,Michael P Geaghan,Roseanne Peel,Stephen Hancock,Elizabeth G Holliday,Murray J Cairns

doi:10.7554/elife.63115

William R Reay, John R Attia + Show 9 more

Open Access

https://doi.org/10.7554/elife.63115

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Abstract

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 polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.

Highlights

Optimal lung function is vital for the ongoing maintenance of homeostasis, with reduced pulmonary function associated with a marked increase in the risk of mortality [1,2]
The previously developed pharmagenic enrichment score framework was implemented to identify druggable pathways enriched with lung function associated variation and calculate pathway specific polygenic scores to prioritise individuals who may benefit from a repurposed compound which interacts with the pathway [12]
We revealed candidate drug repurposing opportunities to potentially improve pulmonary function and provide the means for aligning their application in individuals that carry a high relative burden of variants associated with their function

Summary

Introduction

Optimal lung (pulmonary) function is vital for the ongoing maintenance of homeostasis, with reduced pulmonary function associated with a marked increase in the risk of mortality [1,2]. This is critical due to the considerable number of disorders for which diminished pulmonary function is a clinical hallmark. A transcriptome-wide association study of FEV1 and FVC was undertaken to reveal genes which could be 81 targeted by existing drugs that may increase pulmonary function. An overview schematic of this study is detailed in figure 1 and figure 1 – figure supplement 1

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