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

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 74; no. 8; pp. 1420 - 1429
• Main Authors: Li, Jin, Li, Yun R., Glessner, Joseph T., Yang, Jie, March, Michael E., Kao, Charlly, Vaccaro, Courtney N., Bradfield, Jonathan P., Li, Junyi, Mentch, Frank D., Qu, Hui‐Qi, Qi, Xiaohui, Chang, Xiao, Hou, Cuiping, Abrams, Debra J., Qiu, Haijun, Wei, Zhi, Connolly, John J., Wang, Fengxiang, Snyder, James, Flatø, Berit, Thompson, Susan D., Langefeld, Carl D., Lie, Benedicte A., Munro, Jane E., Wise, Carol, Sleiman, Patrick M. A., Hakonarson, Hakon
• Format: Journal Article
• Language: English
• Published: Boston, USA Wiley Periodicals, Inc 01.08.2022; Wiley Subscription Services, Inc
• Subjects: Annotations; Arthritis; Arthritis, Juvenile - drug therapy; Arthritis, Juvenile - genetics; Gene loci; Gene mapping; Genetic analysis; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Heterogeneity; Humans; Immune system; Joint diseases; Joints (anatomy); Major histocompatibility complex; Network analysis; Phenotypes; Polymorphism, Single Nucleotide; Therapeutic targets
• ISSN: 2326-5191; 2326-5205; 2326-5205
• DOI: 10.1002/art.42129

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.