Rare and common variants in ERAP1 and ERAP2 selected for in response to Yersinia pestis infection contribute to autoimmune disease including inflammatory bowel disease

Endoplasmic reticulum aminopeptidases (ERAP) facilitate antigen presentation. Variation in ERAP1 and ERAP2 genes underwent selection during the Black Death and impact autoimmune disease susceptibility. We assess the burden of functionally impactful variants present in ERAP1 and ERAP2 in 2 cohorts of patients diagnosed with inflammatory bowel disease (IBD; Crohn's disease (CD) or ulcerative colitis (UC)). We analysed the Southampton Genetics of IBD cohort comprising patients diagnosed with IBD, with exome and clinical data on autoimmune comorbidities (n_CD = 661, n_UC = 330); and a subset of UK Biobank IBD patients and selected controls (n_CD = 891, n_UC = 1409, n_control = 60,075). Common single variants (minor-allele-frequency > 0.05) underwent Fisher's exact test with permutations (n = 1000), comparing UC versus CD patients in the Southampton cohort. A gene-burden based test of functionally impactful variants (GenePy) was used to examine rare and common variants in both cohorts. Predicted haplotypes were assessed in each cohort and compared with known haplotypes of ERAP1 and ERAP2. In the Southampton cohort, variant-level analysis identified 6 common variants that were nominally significant when testing between UC versus CD (p < 0.05; empirical permuted p-value). Gene-level analysis using Mann-Whitney-U identified an altered burden of functionally impactful variants for ERAP1 in UC versus CD patients (p = 0.0073), but not for ERAP2. Patients with an isolated diagnosis of UC (p = 0.037,θ = 0.457) vs patients with a concurrent diagnosis of UC and any autoimmune diagnoses had an altered burden of functionally impactful variants in ERAP2. For the UK Biobank cohort, participants diagnosed with UC versus controls had a significantly altered burden of functionally impactful variants in ERAP1 (p = 0.0004) and ERAP2 (p = 0.0006). Both variant and gene-level analysis indicate a role for ERAP1 and ERAP2 in predisposing individuals to developing UC or UC with concurrent autoimmune diagnosis.