LAUSR

BACKGROUND AND AIMS Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopatogenesis involving human leukocyte antigen (HLA)-related immune-mediated responses, environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of CC patients and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC) and celiac disease. METHODS DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on controls and CD, UC and celiac disease cases were provided by the respective Consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score (PRS) calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci (eQTLs) among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS Three HLA alleles (HLA-B*08:01, HLA-DRB1*03:01, and HLA-DQB1*02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1*04:01 on CC risk. PRS quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of eQTLs was detected among the CC susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSION In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD and UC, which supports clinical observations of comorbidity.