Objective Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with juvenile idiopathic arthritis (JIA), the majority of which are located in non-coding regions such as enhancers. This presents a challenge for pinpointing causal variants and their target genes. Interpreting these loci requires functional genomics data from disease-relevant tissues, which has been lacking for JIA. This study seeks to fill that gap and elucidate the biological mechanisms underlying JIA susceptibility. Methods We performed low-input whole genome promoter Capture Hi-C (PCHi-C) and ATAC-seq on CD4+ T cells from three JIA oligoarthritis patients. To link JIA-associated SNPs to potential causal genes, we integrated PCHi-C data with JIA GWAS summary statistics using our Bayesian prioritisation algorithm, Capture Hi-C Omnibus Gene Score (COGS). ATAC-seq was used to further annotate JIA GWAS loci in CD4+ T cells. We then employed CRISPR activation and interference (CRISPRa/i) in Jurkat cells to validate the prioritised SNPs and their corresponding genes. Results Chromatin interactions between JIA-associated SNPs and gene promoters were identified in 19 of 44 non-MHC JIA loci, linking 61 known and novel target genes to the disease. Through COGS, we prioritised seven putative causal genes for JIA: RGS14, ERAP2, HIPK1, CCR4, CCRL2, CCR2, and CCR3. SNPs within promoter-interacting regions (PIRs) of these genes were further validated using CRISPRa/i to confirm their roles in regulating gene expression. Conclusions This study provides insights into the genetic architecture of JIA by integrating genomic and epigenomic data, identifying disease-related genes, functionally validating risk SNPs, and highlighting candidate drugs for repurposing.

Mikhail Spivakov: co-founder and shareholder of Enhanc3D Genomics Ltd

This research is co-funded by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) (NIHR203308), the Wellcome Trust (award references 207491/Z/17/Z and 215207/Z/19/Z),Versus Arthritis (award reference 21754) and the Medical Research Council (MRC) of the UK (MRC Investigator funding MC-A652-5QA20 to MS).The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

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Participants, were recruited under ethics approval granted by the NHS Health Research Authority North West-Greater Manchester West Research Ethics Committee (REC reference: 99/8/084, IRAS ID: 32231). The Committee approved the study, and all participants consented.

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All data produced in the present study are available upon reasonable request to the authors