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.
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
- Murray J Cairns
- Murray J Cairns
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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
- Chris P Ponting, University of Edinburgh, United Kingdom
© 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.
Alternative polyadenylation yields many mRNA isoforms whose 3' termini occur disproportionately in clusters within 3' UTRs. Previously, we showed that profiles of poly(A) site usage are regulated by the rate of transcriptional elongation by RNA polymerase (Pol) II (Geisberg et., 2020). Pol II derivatives with slow elongation rates confer an upstream-shifted poly(A) profile, whereas fast Pol II strains confer a downstream-shifted poly(A) profile. Within yeast isoform clusters, these shifts occur steadily from one isoform to the next across nucleotide distances. In contrast, the shift between clusters from the last isoform of one cluster to the first isoform of the next - is much less pronounced, even over large distances. GC content in a region 13-30 nt downstream from isoform clusters correlates with their sensitivity to Pol II elongation rate. In human cells, the upstream shift caused by a slow Pol II mutant also occurs continuously at the nucleotide level within clusters, but not between them. Pol II occupancy increases just downstream of the most speed-sensitive poly(A) sites, suggesting a linkage between reduced elongation rate and cluster formation. These observations suggest that 1) Pol II elongation speed affects the nucleotide-level dwell time allowing polyadenylation to occur, 2) poly(A) site clusters are linked to the local elongation rate and hence do not arise simply by intrinsically imprecise cleavage and polyadenylation of the RNA substrate, 3) DNA sequence elements can affect Pol II elongation and poly(A) profiles, and 4) the cleavage/polyadenylation and Pol II elongation complexes are spatially, and perhaps physically, coupled so that polyadenylation occurs rapidly upon emergence of the nascent RNA from the Pol II elongation complex.
South Asian women are at increased risk of developing gestational diabetes mellitus (GDM). Few studies have investigated the genetic contributions to GDM risk. We investigated the association of a type 2 diabetes (T2D) polygenic risk score (PRS), on its own, and with GDM risk factors, on GDM-related traits using data from two birth cohorts in which South Asian women were enrolled during pregnancy. 837 and 4372 pregnant South Asian women from the SouTh Asian BiRth CohorT (START) and Born in Bradford (BiB) cohort studies underwent a 75-g glucose tolerance test. PRSs were derived using genome-wide association study results from an independent multi-ethnic study (~18% South Asians). Associations with fasting plasma glucose (FPG); 2 hr post-load glucose (2hG); area under the curve glucose; and GDM were tested using linear and logistic regressions. The population attributable fraction (PAF) of the PRS was calculated. Every 1 SD increase in the PRS was associated with a 0.085 mmol/L increase in FPG ([95% confidence interval, CI=0.07–0.10], p=2.85×10−20); 0.21 mmol/L increase in 2hG ([95% CI=0.16–0.26], p=5.49×10−16); and a 45% increase in the risk of GDM ([95% CI=32–60%], p=2.27×10−14), independent of parental history of diabetes and other GDM risk factors. PRS tertile 3 accounted for 12.5% of the population’s GDM alone, and 21.7% when combined with family history. A few weak PRS and GDM risk factors interactions modulating FPG and GDM were observed. Taken together, these results show that a T2D PRS and family history of diabetes are strongly and independently associated with multiple GDM-related traits in women of South Asian descent, an effect that could be modulated by other environmental factors.