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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.

Type

Journal article

Journal

Nature genetics

Publication Date

10/2012

Volume

44

Pages

1137 - 1141

Addresses

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Keywords

UK Primary Biliary Cirrhosis (PBC) Consortium, Wellcome Trust Case Control Consortium 3, Chromosomes, Human, Pair 19, Humans, Liver Cirrhosis, Biliary, Genetic Predisposition to Disease, Proteins, HLA Antigens, Regression Analysis, Case-Control Studies, Chromosome Mapping, Sequence Analysis, DNA, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, TYK2 Kinase, Genome-Wide Association Study, Genetic Loci