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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.

Original publication

DOI

10.1038/ng.2395

Type

Journal article

Journal

Nat Genet

Publication Date

10/2012

Volume

44

Pages

1137 - 1141

Keywords

Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 19, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA Antigens, Humans, Linkage Disequilibrium, Liver Cirrhosis, Biliary, Polymorphism, Single Nucleotide, Proteins, Regression Analysis, Sequence Analysis, DNA, TYK2 Kinase