P20 The identification of novel genetic susceptibility loci for juvenile idiopathic arthritis by analysis across clinical subgroups
Authors: Bowes John , Marion Miranda C , Smith Samantha , Yarwood Annie , Sudman Marc , Tarasek Damian , Langefeld Carl D , Thompson Susan D , Thomson Wendy 
Published: April 2020

Background

Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of childhood onset inflammatory joint diseases with strong evidence to support a genetic contribution to susceptibility. JIA is divided into seven clinical subgroups based on observed patterns of clinical symptoms using the International League of Associations for Rheumatology (ILAR) classification system. The genetic overlap between these groups is not completely understood and this lack of knowledge typically leads to the different ILAR groups being analysed as discrete entities potentially reducing the power of genetic association studies. The aim of this study was to conduct a large case-control association study on susceptibility to JIA to identify novel susceptibility loci and to investigate differences in these associations between the different ILAR groups for the purposes of maximising power.

Methods

JIA participants were genotyped on the Illumina Infinium CoreExome or OmniExpress arrays. UK population control genotype data was obtained from the Understanding Society Longitudinal Study. Quality control of data was performed conforming to conventional standards and imputation was performed using the Haplotype Reference Consortium panel on the Michigan Imputation Server. Association testing of all SNPs was performed with an additive model incorporating imputation uncertainty using SNPTEST. Testing for specificity and sharing across ILAR groups was performed using Bayesian multinomial regression in the Trinculo software package. Loci passing the suggestive significance threshold (5x10-6) were selected for meta-analysis with previously published JIA GWAS data assuming fixed effects and weighted by inverse-variance using the software package GWAMA.

Results

Following quality control the dataset consisted of &gt; 7.4 million SNPs for 3305 JIA cases and 9196 controls. We found no strong evidence to support association of any SNP to a specific ILAR group with most of the SNPs showing evidence for sharing across multiple groups. Association testing in a combined dataset of all ILAR groups identified seven SNPs associated at genome-wide significance (5x10-8); six of these have previously been reported for JIA while one is a novel association. The novel association (rs497523, p-value = 7.12x10-9) maps to chromosome 16p11 and is located within intron one of the CCDC101 gene. Meta-analysis identified association to rs7647909 which is an intronic variant in the FOXP1 gene (p-value 2.0x10-9) and rs2614258 within the AHI1 gene (p-value 9.5x10-12).

Conclusion

We identified novel associations to SNPs in the CCDC101 and FOXP1 genes. In addition, we report a genome-wide significant association to AHI1, previously reported at suggestive significance levels. Fine mapping with the integration of genomic data will be required to identify the true causal gene at each of these loci. The results provide little evidence to support ILAR subgroup specificity for any of the associated variants and combined analysis of data across subgroups maximised power to identify novel associations.

Disclosures

J. Bowes None. M.C. Marion None. S. Smith None. A. Yarwood None. M. Sudman None. D. Tarasek None. C.D. Langefeld None. S.D. Thompson None. W. Thomson None.