Genetic mechanisms of chronic kidney disease - from candidate gene studies to tissue-multi-omics

Abstract

Chronic kidney disease (CKD) is a significant global health burden that impacts almost 10% of the global population and is growing as a leading cause of death across the world. It is responsible for millions of deaths per year and current therapeutics have proven unsuitable to reverse this trend. CKD and its defining traits have demonstrated a strong heritable component, prompting investigation into the underlying genetic architecture of the disease. Traditionally, candidate gene studies have been the primary approach to elucidating disease mechanisms, and have generated novel hypotheses and insights into the underlying pathology of CKD. More recently, the genome-wide approach - particularly transcriptomics - has begun to unravel the complex genetic nature of CKD. Analysis of candidate gene LRG1 (leucine-rich a-2-glycoprotein 1) implicated it as a component of the renal immune system and a putative mediator of kidney function. In addition, through leveraging transcriptome-wide association studies (TWAS) of CKD-defining traits in the human kidney and integration of publicly-available genetic and clinical annotations, I prioritised 186 genes associated with CKD, 93 of which were not detected in previous kidney TWAS. These were validated through the recapitulation of well-known kidney genes and SLC7A9 (solute carrier family 7 member 9) was identified as a novel putative contributor to CKD. Furthermore, 1,459 kidney microRNAs (miRNA) underwent genetic and transcriptomic characterisation and a kidney TWAS of CKD-defining traits identified 13 miRNAs significantly associated with CKD. Specifically, miR-548ah-5p and miR-1307-3/5p emerged as candidates of interest with strong associations with CKD that warrant further functional studies. Moreover, exploration into the contributions of renal DNA methylation to kidney function - facilitated by colocalisation and Mendelian randomisation (MR) - uncovered 73 independent genomic regions associated with DNA methylation and CKD-defining traits as well as uncovered a novel putative association between transcription factor UNCX (UNC homeobox) and CKD-defining traits which is causally mediated by DNA methylation. In summary, the findings presented in this thesis provide critical insights into the biological underpinnings of CKD and identify therapeutic candidates relevant to CKD-defining traits with the potential to facilitate the development of novel therapeutics in the future.

Date of Award	6 Jan 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Nicholas Ashton (Supervisor), James Eales (Supervisor), Sabu Abraham (Supervisor) & Maciej Tomaszewski (Supervisor)