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Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

Lookup NU author(s): Professor Heather CordellORCiD, Samantha Ducker, Dr Peter Donaldson, Professor David Jones

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Abstract

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 x 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; r(2) > 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 (r(2) > 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.

Publication metadata

Author(s): 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

Publication type: Letter

Publication status: Published

Journal: Nature Genetics

Year: 2012

Volume: 44

Issue: 10

Pages: 1137-1141

Print publication date: 01/10/2012

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: NATURE PUBLISHING GROUP

URL: http://dx.doi.org/10.1038/ng.2395

DOI: 10.1038/ng.2395

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