Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.
Liu JZ., Almarri MA., Gaffney DJ., Mells GF., Jostins L., Cordell HJ., Ducker SJ., Day DB., Heneghan MA., Neuberger JM., Donaldson PT., Bathgate AJ., Burroughs A., Davies MH., Jones DE., Alexander GJ., Barrett JC., Sandford RN., Anderson CA.
We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P<5×10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2>0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.