The Immunochip is a custom genotyping array designed for fine-mapping and replication of loci identified in genome-wide association studies of 12 immune-mediated disorders. The array is made up of 196,524 markers, the majority of which lie in 186 regions with known associations with disease. Using the Immunochip, we performed association studies in two immune-mediated liver disorders: primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).
For PBC, we genotyped 2,861 cases and 8,514 controls from the UK. We identified 18 genome-wide significant (P<5´10-8) susceptibility loci, of which 3 are novel. The most strongly associated novel variant at 19p12 is a low-frequency nonsynonmous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. Multiple independent common, low-frequency and rare variants were identified in 5 loci. Integrating association results with functional data from the ENCODE project revealed a modest enrichment of regulatory regions in B-lymphoblastoid cell lines among the associated loci.
For PSC, we genotyped 3,789 cases and 25,079 controls from across Europe and North America. Twelve genome-wide significant PSC susceptibility loci were identified, of which 9 are novel. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the patients, six of the 12 loci showed significantly stronger association with PSC than IBD, suggesting an overlapping yet distinct genetic architecture. We incorporated pleiotropy with seven diseases clinically co-occurring with PSC in an extended analysis, finding suggestive evidence for 33 additional PSC risk loci.
Together, these studies demonstrate how integrating fine-mapping association results with functional genomic data and associations with related diseases can offer insights into the genetic architecture and etiology of disease.