Functional and computational interrogation of juvenile idiopathic arthritis risk loci in CD4+ T cells

Genome-wide association studies (GWASs) have identified multiple genetic regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single-nucleotide polymorphisms (SNPs) that drive disease risk has been impeded by the fact that the SNPs used to identify risk loci are in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and thus use genetic information to elucidate disease biology and inform patient care. We next used existing genotyping data from 3,939 children with JIA and 14,412 healthy controls to identify SNPs on JIA-risk haplotypes that present within open chromatin in multiple immune cell types and are more common in children with JIA than the controls (p < 0.05) in the genotyping datasets. We identified SNPs within cis-regulatory regions (cis-regulatory elements [CREs]) using precision run-on sequencing data and identified likely target genes using MicroC in both resting and activated CD4+ T cells. We identified 138 SNPs within the PROseq-identified CREs and n = 41 genes with which these CREs physically interacted. Data from Genotype-Tissue Expression (GTEx) and the Database of Immune Cell Expression Quantitative Trait Loci (DICE) corroborated these analyses by showing allelic effects for SNPs within the CREs in the ERAP2/LNPEP and locus. We further corroborated IRF1 allelic effects using a luciferase reporter assay. Our findings significantly reduce the genomic search space for risk-driving variants and target genes and support the roles of IRF1, ERAP2, and LNPEP in driving risk for JIA.