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Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis
Jimmy Z Liu,1, 12 Mohamed A Almarri,1, 12 Daniel J Gaffney,1 George F Mells,2, 3 Luke Jostins,1 Heather J Cordell,4 Samantha J Ducker,5 Darren B Day,2 Michael A Heneghan,6 James M Neuberger,7 Peter T Donaldson,5 Andrew J Bathgate,8 Andrew Burroughs,9 Mervyn H Davies,10 David E Jones,5 Graeme J Alexander,3 Jeffrey C Barrett,1 The UK Primary Biliary Cirrhosis (PBC) Consortium, The Wellcome Trust Case Control Consortium 3, Richard N Sandford2, 13 Carl A Anderson1, 13
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.
