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Association of novel rare coding variants with juvenile idiopathic arthritis
  1. Xinyi Meng1,
  2. Xiaoyuan Hou1,
  3. Ping Wang1,
  4. Joseph T Glessner2,
  5. Hui-Qi Qu2,
  6. Michael E March2,
  7. Sipeng Zhang1,
  8. Xiaohui Qi1,
  9. Chonggui Zhu3,
  10. Kenny Nguyen2,
  11. Xinyi Gao1,
  12. Xiaoge Li4,
  13. Yichuan Liu2,
  14. Wentao Zhou1,
  15. Shuyue Zhang1,
  16. Junyi Li1,
  17. Yan Sun1,
  18. Jie Yang1,
  19. Patrick M A Sleiman2,5,6,
  20. Qianghua Xia1,
  21. Hakon Hakonarson2,5,6,
  22. Jin Li1,7,8
  1. 1Department of Cell Biology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
  2. 2Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  3. 3Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
  4. 4Department of Pediatrics, Jinnan Hospital, Tianjin, China
  5. 5Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  6. 6Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  7. 7Tianjin Eye Hospital, Tianjin, China
  8. 8Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China
  1. Correspondence to Dr Jin Li, Department of Cell Biology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; jli01{at}; Dr Hakon Hakonarson, Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; hakonarson{at}; Dr Qianghua Xia, Department of Cell Biology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; qhxia{at}


Objective Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children, but a few studies have investigated the contribution of rare variants to JIA. In this study, we aimed to identify rare coding variants associated with JIA for the genome-wide landscape.

Methods We established a rare variant calling and filtering pipeline and performed rare coding variant and gene-based association analyses on three RNA-seq datasets composed of 228 JIA patients in the Gene Expression Omnibus against different sets of controls, and further conducted replication in our whole-exome sequencing (WES) data of 56 JIA patients. Then we conducted differential gene expression analysis and assessed the impact of recurrent functional coding variants on gene expression and signalling pathway.

Results By the RNA-seq data, we identified variants in two genes reported in literature as JIA causal variants, as well as additional 63 recurrent rare coding variants seen only in JIA patients. Among the 44 recurrent rare variants found in polyarticular patients, 10 were replicated by our WES of patients with the same JIA subtype. Several genes with recurrent functional rare coding variants have also common variants associated with autoimmune diseases. We observed immune pathways enriched for the genes with rare coding variants and differentially expressed genes.

Conclusion This study elucidated a novel landscape of recurrent rare coding variants in JIA patients and uncovered significant associations with JIA at the gene pathway level. The convergence of common variants and rare variants for autoimmune diseases is also highlighted in this study.

  • arthritis
  • juvenile
  • autoimmune diseases
  • polymorphism
  • genetic

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  • Handling editor Josef S Smolen

  • XH and PW contributed equally.

  • Contributors XM was mainly involved in the data analysis, processing and summarisation. XH and PW were mainly responsible for drafting manuscript. QX, HH and JL were responsible for conception and design of study and revising the manuscript critically for important intellectual content. Other authors have partially participated in the study. All listed authors have seen and approved the manuscript.XH and PW are co-second authors.

  • Funding This project was funded by National Natural Science Foundation of China (No.81771769), Natural Science Foundation of Tianjin (No.18JCYBJC42700) and the Institute Development Funds to the Centre for Applied Genomics at CHOP.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Ethical approval for this study was obtained from CHOP Institutional Review Board (CHOP IRB#4886) and carried out in accordance with the nationally approved guidelines.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. Data are available on reasonable request. Three RNA-seq datasets are from public database the Gene Expression Omnibus (GSE79970, GSE81259 and GSE112057). Whole-exome sequencing data are available upon reasonable request. All data requests should be addressed to HH.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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