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

eLife

John R Attia¹  Elizabeth G Holliday¹  Stephen Hancock¹  Roseanne Peel¹  Carlos Riveros¹  Mark A McEvoy¹  Sahar I El Shair²  Murray J Cairns³  Michael P Geaghan³  Rodney J Scott³  William R Reay³ 

[1] Hunter Medical Research Institute, Newcastle, Australia;School of Medicine and Public Health, The University of Newcastle, Callaghan, Australia;School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, Australia;School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, Australia;Hunter Medical Research Institute, Newcastle, Australia;

关键词: GWAS;    causal inference;    TWAS;    drug repurposing;    lung function;    polygenic scoring;    Human;   

DOI  :  10.7554/eLife.63115

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY