Genomic risk scores for juvenile idiopathic arthritis and its subtypes

Abstract

Aims: Juvenile idiopathic arthritis (JIA) is an autoimmune disease and a common cause of chronic disability in children. Diagnosis of JIA is based purely on clinical symptoms, leading to treatment delays. Despite JIA having substantial heritability, the construction of genomic risk scores (GRSs) to aid or expedite diagnosis has not been assessed. Here, we generate GRSs for JIA and its subtypes and evaluate their performance. Methods: We examined three case/control cohorts (UK, US, and Australia) with genome-wide single nucleotide polymorphism (SNP) genotypes. We trained GRSs for JIA and its subtypes using lasso-penalised linear models in cross-validation on the UK cohort, and externally tested in the Australian and US cohorts. Results: The JIA GRS alone achieved cross-validated AUC=0.670 in the UK cohort and externally validated AUCs of 0.657 and 0.671 in US-based and Australian cohorts, respectively. In logistic regression of case/control status, the corresponding odds ratios per standard deviation (s.d.) of GRS were 1.831 [1.685-1.991] and 2.008 [1.731-2.345], and were unattenuated by adjustment for sex or the top 10 genetic principal components. Extending our analysis to JIA subtypes revealed that enthesitis-related JIA had both the longest time-to-referral and the subtype GRS with the strongest predictive capacity overall across datasets: AUCs 0.80 in UK; 0.83 Australian; 0.69 US-based. The particularly common oligoarthritis JIA subtype also had a subtype GRS outperformed those for JIA overall, with AUCs of 0.71, 0.75 and 0.77, respectively. Conclusions: A genomic risk score for JIA has potential to augment purely clinical JIA diagnosis protocols, prioritising higher-risk individuals for follow-up and treatment. Consistent with JIA heterogeneity, subtype-specific GRSs showed particularly high performance for enthesitis-related and oligoarthritis JIA.

Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps

“…A celiac disease PRS improves upon HLA typing alone [17][18][19] , and pilot clinical studies indicate improved effectiveness and cost-efficiency for celiac diagnosis, potentially reducing invasive diagnostic procedures 20 . For juvenile idiopathic arthritis and its subtypes, PRS may substantially improve upon clinical diagnosis, potentially reducing long waiting periods for diagnosis and treatment 21 . Furthermore, a PRS for ankylosing spondylitis has been shown to have high diagnostic capacity (AUROCs of 0.92 and 0.94 in European and East Asian ancestries, respectively) and potential clinical utility for earlier and cost-effective diagnosis if combined with magnetic resonance imaging 22 .…”

Clinical application of personalized rheumatoid arthritis risk information: translational epidemiology leading to precision medicine

“…A traditional view of epidemiology uses risk factors to passively elucidate an overall disease process or identify trends on a population level. In the context of precision medicine, epidemiologic findings may be used to deconstruct disease heterogeneity [4] while informing the development and implementation of personalized interventions [5], or 'translational epidemiology.' This article illustrates two recent translational epidemiologic studies in rheumatology that sought to incorporate personalized risk factors into a clinical framework leading us closer toward precision medicine.…”