Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis

Abstract

Objective: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes.

Methods: We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses.

Results: In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types.

Conclusion: This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.

Figure 1

Distribution of juvenile idiopathic arthritis (JIA) subtypes represented in our JIA case–control cohort. RF = rheumatoid factor. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42129/abstract.

Figure 2

Manhattan plot showing association statistics for the heterogeneity‐sensitive genome‐wide association study of juvenile idiopathic arthritis subtypes, with adjustment for multiple testing. Candidate gene symbols for genome‐wide significant loci are shown, with novel loci indicated in red. Symbols represent individual genes. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42129/abstract.

Figure 3

Regional association plots showing novel juvenile idiopathic arthritis genome‐wide significant loci. Color‐coded symbols represent individual genes showing an association at different thresholds of significance. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42129/abstract.