Analysis of the ImmunoChip single nucleotide polymorphism (SNP) array in 2816 individuals, comprising the most common subtypes (oligoarticular and RF negative polyarticular) of juvenile idiopathic arthritis (JIA) and 13056 controls strengthens the evidence for association to three known JIA-risk loci (HLA, PTPN22 and PTPN2) and has identified fourteen risk loci reaching genome-wide significance (p < 5 × 10-8) for the first time. Eleven additional novel regions showed suggestive evidence for association with JIA (p < 1 × 10-6). Dense-mapping of loci along with bioinformatic analysis has refined the association to one gene for eight regions, highlighting crucial pathways, including the IL-2 pathway, in JIA disease pathogenesis. The entire ImmunoChip loci, HLA region and the top 27 loci (p < 1 × 10-6) explain an estimated 18%, 13% and 6% risk of JIA, respectively. Analysis of the ImmunoChip dataset, the largest cohort of JIA cases investigated to date, provides new insight in understanding the genetic basis for this childhood autoimmune disease.

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases characterized by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2,566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of dermatomyositis (DM, n=879), juvenile dermatomyositis (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (IBM, n=252) patients collected from 14 countries through the Myositis Genetics Consortium. The human leukocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10−8). Nine regions were associated at a significance level of p<2.25×10−5, including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM, and JDM. This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.