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

Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.

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<5×10(-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • HLA Antigens
  • Intracellular Signaling Peptides and Proteins
  • LNK protein, human
  • Proteins
  • TYK2 Kinase
  • TYK2 protein, human