title: Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Jimmy Z
authors.initials: JZ
authors.lastname: Liu
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Almarri
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gaffney
authors.forename: George F
authors.initials: GF
authors.lastname: Mells
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Ducker
authors.forename: Darren B
authors.initials: DB
authors.lastname: Day
authors.forename: Michael A
authors.initials: MA
authors.lastname: Heneghan
authors.forename: James M
authors.initials: JM
authors.lastname: Neuberger
authors.forename: Peter T
authors.initials: PT
authors.lastname: Donaldson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bathgate
authors.forename: Andrew
authors.initials: A
authors.lastname: Burroughs
authors.forename: Mervyn H
authors.initials: MH
authors.lastname: Davies
authors.forename: David E
authors.initials: DE
authors.lastname: Jones
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Alexander
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sandford
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008105:Liver Cirrhosis, Biliary / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D012044:Regression Analysis; D017422:Sequence Analysis, DNA; D053634:TYK2 Kinase / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006680:HLA Antigens; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human; D053634:TYK2 Kinase; C070139:TYK2 protein, human