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Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.
- Source :
-
Nature genetics [Nat Genet] 2012 Oct; Vol. 44 (10), pp. 1137-41. Date of Electronic Publication: 2012 Sep 09. - Publication Year :
- 2012
-
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.
- Subjects :
- Adaptor Proteins, Signal Transducing
Case-Control Studies
Chromosome Mapping
Chromosomes, Human, Pair 19
Gene Frequency
Genetic Loci
Genome-Wide Association Study
Genotype
HLA Antigens genetics
Humans
Intracellular Signaling Peptides and Proteins
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Proteins genetics
Regression Analysis
Sequence Analysis, DNA
Genetic Predisposition to Disease
Liver Cirrhosis, Biliary genetics
TYK2 Kinase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 44
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 22961000
- Full Text :
- https://doi.org/10.1038/ng.2395