P18 Investigating the role of rare genetic variants and susceptibility to juvenile idiopathic arthritis highlights the importance of monogenic disease genes

Abstract Background Juvenile idiopathic arthritis (JIA) is a rheumatic disease, onset before the age of sixteen. JIA is a common complex disease, with contributions from both genetic and environmental risk factors. However, given the young age of onset for JIA, it is possible that genetic risk factors influence susceptibility to a greater extent than environmental risk factors. While several susceptibility loci have been identified for JIA, they are mainly genetic variants that are common in the population. The role of rare genetic variants has not yet been fully explored in JIA. Therefore, the aims of this research were to use rare (<5%MAF) variant based analysis to further define the genetic architecture of JIA. Methods A total of 2,162 UK JIA cases were genotyped using the Illumina HumanCoreExome array and the Understanding Society’s UK household longitudinal study provided the genotype data for 9196 controls. Single variant analysis was used to calculate the association of variants to JIA susceptibility. Gene-based aggregation analysis, specifically the SKAT-O method, were used to calculate the association of whole gene regions to JIA cases. This gene-based aggregation method increases the statistical power of associations, which is valuable when attempting to identify rare variants. Study-wide significance for this research was calculated using a Bonferroni corrected threshold (P = 3.34x10-6). Results Several strongly associated candidate gene regions were identified using SKAT-O analysis. Firstly, the region mevalonate kinase (MVK) (P = 3.95x10-10) was found to be strongly associated. MVK has been reported in mevalonate kinase deficiency, a rare juvenile disease with a phenotype akin to systemic JIA. PYCR1 (P = 1.97x10-9) was an additional region of interest. Variants in this region have been reported in geroderma osteodysplasticum; a disease that results in dysplasia of the hips, hyperextensible joints and skeletal changes. The region WISP3 (P = 8.52x10-9) was also strongly associated. Variants from this region have previously been reported in progressive pseudorheumatoid dysplasia; a disease that can be clinically misdiagnosed with JIA due to similarities in phenotypes. Furthermore, LILRA2 (P = 2.89x10-7) presented as a strong candidate region, with the gene being upregulated in synovial tissue of rheumatoid arthritis patients. Conclusion This analysis has identified promising candidate genes that influence susceptibility to JIA and highlights two key points. Firstly, gene-burden tests of rare variants have the potential to identify novel susceptibility genes for juvenile-onset disease. While MVK and WISP3 have previously been reported to be associated with JIA, these associations were modest, and the current study provides compelling evidence to support their importance. Secondly, the results highlight the importance of investigating the contribution of monogenic genes in juvenile-onset common complex disease. Disclosures M.K. Tordoff None. T.A. Briggs None. S.L. Smith None. A. Yarwood None. W. Thomson None. J. Bowes None.