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

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

The following previously published data sets were used

Article and author information

Author details

  1. William R Reay

    School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
    Competing interests
    William R Reay, has filed a patent related to the use of the pharmagenic enrichment score methodology in complex disorders. This competing interest only applies to that section of the manuscript. WIPO Patent Application WO/2020/237314..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7689-2453
  2. Sahar I El Shair

    School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  3. Michael P Geaghan

    School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  4. Carlos Riveros

    School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  5. Elizabeth G Holliday

    School of Medicine and Public Health, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  6. Mark A McEvoy

    School of Medicine and Public Health, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  7. Stephen Hancock

    School of Medicine and Public Health, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  8. Roseanne Peel

    School of Medicine and Public Health, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  9. Rodney J Scott

    School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  10. John R Attia

    School of Medicine and Public Health, University of Newcastle, Callaghan, Australia
    Competing interests
    No competing interests declared.
  11. Murray J Cairns

    School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia
    For correspondence
    murray.cairns@newcastle.edu.au
    Competing interests
    Murray J Cairns, has filed a patent related to the use of the pharmagenic enrichment score methodology in complex disorders. This competing interest only applies to that section of the manuscript. WIPO Patent Application WO/2020/237314..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2490-2538

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

Reviewing Editor

  1. Chris P Ponting, University of Edinburgh, United Kingdom

Publication history

  1. Received: September 15, 2020
  2. Accepted: March 11, 2021
  3. Accepted Manuscript published: March 15, 2021 (version 1)
  4. Version of Record published: April 21, 2021 (version 2)

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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  1. William R Reay
  2. Sahar I El Shair
  3. Michael P Geaghan
  4. Carlos Riveros
  5. Elizabeth G Holliday
  6. Mark A McEvoy
  7. Stephen Hancock
  8. Roseanne Peel
  9. Rodney J Scott
  10. John R Attia
  11. Murray J Cairns
(2021)
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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