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

Jin Li, Yun R. Li, Joseph T. Glessner, Jie Yang, Michael E. March, Charlly Kao, Courtney N. Vaccaro, Jonathan P. Bradfield, Junyi Li, Frank D. Mentch, Hui Qi Qu, Xiaohui Qi, Xiao Chang, Cuiping Hou, Debra J. Abrams, Haijun Qiu, Zhi Wei, John J. Connolly, Fengxiang Wang, James SnyderBerit Flatø, Susan D. Thompson, Carl D. Langefeld, Benedicte A. Lie, Jane E. Munro, Carol Wise, Patrick M.A. Sleiman, Hakon Hakonarson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1420-1429
Number of pages10
JournalArthritis and Rheumatology
Volume74
Issue number8
DOIs
StatePublished - Aug 2022

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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