Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs. The pathogenesis of SLE is multifactorial including genetic, environmental, and hormonal factors. Genome wide association studies (GWAS) have transformed our understanding of SLE’s genetic aetiology. Over 100 loci have been confirmed to show robust association with SLE. However, the functional effects through which these variants elevate disease risk is limited.My objective was to validate and search for additional susceptibility loci for SLE using a meta-analysis of individual-level data from three GWAS cohorts and one Immunochip cohort of European ancestry. Through functional annotation from multiple heterogeneous sources and statistical fine mapping of the loci, I sought to establish 'causal' genes at a trait-associated locus and the biological processes thereby implicated in the pathogenesis of SLE.
I performed a meta-analysis of three GWAS SLE cohorts and one Immunochip SLE cohort (32266 including 9302 cases and 22854 controls). I compared the published Immunochip SLE association results with my meta- analysis results, defined criteria for novel loci, and summarized all candidate loci. Utilizing quantitative trait loci (eQTLs, pQTLs and mQTLs) and other functional genomics data chromatin conformation and chromatin interactions, I performed two-sample Mendelian randomisation (MR) and colocalisation, to identify putatively causal effects between trait and lupus, enabling biological insight and prioritizing genes at lupus candidate loci.
I identified 61 SLE risk loci, including three novel loci (1q21.3, 2q12.1, 11q22.3) at genome-wide significance (p≤5E−08). Using conditional and joint association analysis, I mapped 118 association signals within these loci. Bayesian statistical fine-mapping analysis was used to prioritize credible sets of casual variants for enrichment analysis. The results of which showed preferential enrichment with epigenetic activation marks in B cells. Combining the colocalisation with MR analyses, I identified 481 tissue-specific cis eQTL that mapped to the SLE risk loci. Fourteen pQTL also mapped to these same regions as well as 11 mQTL.
The three novel loci I identified had significant MR results using eQTL as instrumental variables: ADAM15, IL18R1, MCPIP3 (ZC3H12C). A similar MR analysis with plasma pQTL identified two plasma proteins: IL18R1 and IL1RL1 at the 2q12.1 locus. The risk allele in this locus for lupus increases the functional activity of IL18R1 and IL1RL1. The Interleukin-18 Receptor 1 (IL18R1) specifically binds to Interleukin 18 (IL18), which is a pro- inflammatory cytokine that promotes Type I T helper cell activity. IL-18 has hitherto not been established as playing a role in SLE pathogenesis. Soluble IL1RL1, Interleukin 1 Receptor Like 1 (ST2) has been shown to reduce experimental allergic airway inflammation through ST2/IL-33 pathway. This suggests that at this locus, SLE susceptibility and asthma are reciprocally driven by genetic factors.
In summary, I identified three novel genetic loci and use MR and colocalisation approach to identify and prioritize casual genes in novel and published lupus loci. I found shared genetic mechanism of lupus with asthma, which can contribute to potential therapeutic targets.
| Date of Award | 1 Feb 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Timothy Vyse (Supervisor) & David Morris (Supervisor) |