Applying ‘omics to understand and predict juvenile idiopathic arthritis

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatic condition, postulated to be caused by an environmental trigger in genetically susceptible individuals. There remain significant knowledge gaps regarding aetiology and prognosis. Observational epidemiology studies are challenging in rare diseases, due to limited sample sizes and study biases. Genetic epidemiology methods can mitigate some of these biases, but their application in paediatric rheumatology has been limited. In other areas of medicine, genetic epidemiology has contributed to knowledge of disease causation, prognosis/outcome, biomarkers, and therapeutic targets.

This thesis harnesses recent genomic datasets and methodological developments to advance knowledge of JIA. For the first time, environmental factors associated with JIA risk are collated and quantified using systematic review and meta-analysis. The output of this work informed innovative research into JIA causation using Mendelian randomisation (MR). Genetic correlation analysis using linkage disequilibrium score regression was used to explore health outcomes associated with JIA, with MR employed to explore causal relationships between JIA and highly correlated, non-autoimmune traits. Pairwise, cross-disorder, genome wide meta-analyses exploited the shared genetic architecture between JIA and autoimmune diseases, aiding the discovery of 12 new genomic loci associated with JIA risk. The genetic correlation between JIA and coronary artery disease was explored using polygenic risk scores, which found strong associations between JIA polygenic risk and multiple cardiovascular phenotypes in early life.

The complementary use of traditional observational and contemporary genetic epidemiology techniques, combined with both hypothesis-driven and hypothesis-free research in this thesis has generated multiple, novel findings related to both the causes and consequences of JIA. The clinical implications of these findings include a) the identification of new environmental and genetic factors associated with JIA onset, b) the adverse cardiovascular risk profile in JIA, and c) the potential need to screen patients for cardiovascular risk factors and co-existent autoimmunity.
Date of Award27 Sept 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorCaroline L Relton (Supervisor), Athimalaipet V Ramanan (Supervisor), Gemma C Sharp (Supervisor) & You Zhou (Supervisor)

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