A genome-wide association study for juvenile idiopathic arthritis identifies chromosome region 3q13 near the T cell receptor co-stimulatory molecule CD80

Abstract

Objective: Juvenile idiopathic arthritis (JIA) is a complex genetic trait. Like other autoimmune diseases, JIA has strong HLA associations, and is often found in families with a history of other autoimmune diseases. Furthermore, many of the loci associated with JIA are shared across several autoimmune diseases. Here we report a large genome-wide association study of oligoarticular and polyarticular rheumatoid factor negative forms of JIA. Methods: The Discovery Cohort consisted of 814 JIA cases, 658 local controls and 2400 out-of-study controls from the Non-Gain Schizophrenia Study who self-identified as Non-Hispanic, European ancestry. The Replication Cohort consisted of 1621 cases and 1630 controls representing five independent JIA case and control sample collections originating from the United Kingdom (CAPS and BSPAR study group), Germany, Utah, Delaware or Texas. Additional out-of-study controls were available for the UK cohort (Wellcome Trust Case Control Consortium, n=5984) and used in the replication analysis. For the Discovery Cohort, genotyping was done using the Affymetrix SNP Array 6.0 and tests for association were adjusted for potential confounding affects of population structure via covariates in logistic regression models. Analyses were repeated adjusting for key HLA associations. Ten SNPs representing five loci, which to our knowledge have not yet been reported in JIA, were selected based on statistical evidence and biologic information and genotyped by Taqman or Sequenom chemistries in the Replication Cohort. Association testing and meta-analyses were performed. Results: Testing for genome-wide association in the Discovery Cohort identified multiple loci outside the MHC region associated with JIA. Previously identified loci associated with JIA and overlapping with other autoimmune disease associations include PTPN22 (rs6679677, p=1.98×10-12, rs2476601, p=1.90×10-13and rs2488457, p=6.74×10-8), and PTPN2 (rs1893217, p=1.60×10-9and rs7234029, p=1.86×10-10). Novel loci with consistent findings in both the Discovery and Replication cohorts are shown in the table and include c3orf1, IL15, and REEP3. (Figure presented)Conclusions: We provide strong evidence in both the Discovery Cohort and Replication Cohort for a novel autoimmune disease and JIA association with 3q13, a region containing the TCR co-stimulatory molecule CD80. Fine mapping and integration with gene expression data is underway to further define this locus.