Understanding disease relationships with idiopathic pulmonary fibrosis through genomic methods
File(s)
Author(s)
Moss, Samuel
Type
Thesis
Abstract
Idiopathic pulmonary fibrosis is a disease characterised by uncontrolled lung scarring, lung function decline, and a poor prognosis. Current treatments for IPF are limited and can only slow disease progression. To add to this problem, the biology underlying IPF disease is incompletely understood. This thesis aims to investigate how the genetics of IPF are linked to other human diseases, traits, and biological features to provide insights into disease mechanisms and potentially highlight opportunities for novel IPF treatments. A phenome-wide association study (PheWAS) was conducted to investigate the spectrum of phenotypes associated with IPF genetic risk variants. This investigation highlighted shared genetic variants associated with IPF risk and multiple traits including lung function, telomere length, and total testosterone measurements. Using genetic correlation, broad genetic overlap across IPF and related traits was also evaluated. This analysis identified the overlap of genetics associated with telomere length, lung function, and primary biliary cholangitis with genetics of IPF susceptibility. Finally, a Mendelian randomisation approach was used to assess if the epidemiological association between IPF and diabetes mellitus is driven by direct causal effects between these diseases. Overall, no evidence of causal effects was suggested, indicating that other factors such as treatment effects may be driving this epidemiological relationship. In addition, a similar Mendelian randomisation approach was applied to investigate if a potential biological relationship between mosaic loss of Y chromosome (mLOY) and IPF is driven by direct causal effects. This investigation did not identify any evidence of causal effects between mLOY and IPF but highlights that shortened telomere length may be a central factor driving both traits.
Version
Open Access
Date Issued
2024-08-25
Date Awarded
01/06/2025
License URL
Advisor
Jenkins, Gisli
Stewart, Iain
Sponsor
National Institute for Health Research (Great Britain)
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)