Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function
- University of Newcastle, Australia
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 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.
Data availability
All data are publicly available from the references described in the manuscript. Code related to this study can be found at the following link: https://github.com/Williamreay/Lung_function_drug_repurposing_manuscript
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GWAS summary statistics - lung functionGWAS Catalog, GCST007429, GCST007432, GCST007431,.
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GEUVADISArrayExpress, E-GEUV-1.
Article and author information
Author details
Funding
National Health and Medical Research Council (1147644)
- Murray J Cairns
National Health and Medical Research Council (1121474)
- Murray J Cairns
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The use of the Hunter Community Cohort data was approved by the University of Newcastle Human Ethics Research Committee (HREC, reference: H-820-0504a). All other information related to ethical approval for the individual GWAS studies we utilised in this study are detailed in their respective publications as referenced throughout the text
Copyright
© 2021, Reay et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function
eLife 10:e63115.
https://doi.org/10.7554/eLife.63115
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