Multi-omics Mendelian randomization using different molecular traits to identify novel drug targets on complex diseases

Abstract

The growth of molecular quantitative trait loci (mQTLs) in recent years has provided great opportunities in unraveling the biology of complex diseases. I employed a variety of molecular traits across epigenome, transcriptome and proteome to identify novel drug targets on complex diseases.
In Chapter 3, I applied 2SMR and colocalization with sQTLs to identify putative splicing events on breast, lung, ovarian and prostate cancer across 49 tissues from GTEX. The top MR associations showed different splicing-type enrichment patterns across different cancers, providing information for mechanism exploration and drug target prioritization for cancer prevention.

In Chapter 4, I constructed a multi-ancestry proteome-wide MR analysis pipeline based on pQTLs from GBMI. 16 protein-disease pairs were prioritized for investigation in future drug trials with causal evidence in cross-ancestry or in specific ancestry. The result highlights the value of proteome-wide MR in exploring drug targets for disease prevention across ancestries.

In Chapter 5, I evaluated the effects of genetically predicted gene expression for 16,358 gene-immune cell pairs (sc-eQTLs) on 13 cancer outcomes and identified nine gene-disease pairs with high drug development value. Besides, Literature-derived protein interactor networks were constructed with immune related genes, providing opportunities to observe immune landscapes with MR causal information.

In Chapter 6, I used multi-omics colocalization to detect pleiotropy status in gene regions with clear MR evidence. Three independent signal groups were discovered in CASP8 gene region which have shared causal variants between more than two kinds of molecular traits and prostate cancer outcome, suggesting future investigation in molecular function change and drug target specification.

This thesis employs different molecular traits to detect potential causal relationships in complex diseases and discover novel drug targets, offering insights into the underlying biological mechanisms linking specific molecular pathways to disease outcomes and helping guide the development of targeted therapies.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Tom R Gaunt (Supervisor), Gibran Hemani (Supervisor) & Jie Zheng (Supervisor)