Sex-stratified autosomal association analysis reveals dimorphic genetic risk factors in non-systemic juvenile idiopathic arthritis.

Objectives Juvenile idiopathic arthritis (JIA) is a collection of childhood onset rheumatic conditions that more frequently occur in females in most subtypes. Sex influences disease biology, treatment trajectories, and patient outcomes, however, no study to date has investigated the interaction of sex with autosomal genetic risk to JIA. Methods Genotype data from 3748 JIA cases (2551 female, 1197 male) and 9196 controls (5136 female, 4060 male) were analysed using a sex-stratified genome-wide association analysis. Systemic JIA was excluded. HLA imputation and fine-mapping were performed using SNP2HLA. Sex-specific effects were assessed using an omnibus sex-interaction test for multi-allelic amino acid positions. A subtype specific analysis was repeated in rheumatoid factor (RF) negative polyarthritis and oligoarthritis (1862 female, 718 male). Results A sex-combined analysis identified genome-wide significant (P<5x10-8) loci across the HLA region and nine loci outside the HLA region, including a novel association at rs231977 (NUPR1). Markers within the HLA region were significantly sex-dimorphic (P<5x10-8) and nine loci outside of the HLA region were suggestive for sex dimorphism (P<5x10-6), including SPRY2. HLA fine-mapping identified lysine at position 70 of HLA-B conferring greater male JIA risk, and tyrosine at position 10 of HLA-DRB1 conferring greater female JIA risk. Subtype specific analysis strengthened the association of tyrosine at position 10 of DRB1 in females. Conclusions This study provides the first evidence that autosomal genetic risk factors contribute to JIA risk in a sex-dimorphic manner, mirroring known clinical observations, and highlighting the importance of incorporating sex-stratified methods in future JIA studies.