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

被引：217

作者：

Liu, Jimmy Z. ^{[1
]}

Almarri, Mohamed A. ^{[1
]}

Gaffney, Daniel J. ^{[1
]}

Mells, George F. ^{[2
,3
]}

Jostins, Luke ^{[1
]}

Cordell, Heather J. ^{[4
]}

Ducker, Samantha J. ^{[5
]}

Day, Darren B. ^{[2
]}

Heneghan, Michael A. ^{[6
]}

Neuberger, James M. ^{[7
]}

Donaldson, Peter T. ^{[5
]}

Bathgate, Andrew J. ^{[8
]}

Burroughs, Andrew ^{[9
]}

Davies, Mervyn H. ^{[10
]}

Jones, David E. ^{[5
]}

Alexander, Graeme J. ^{[3
]}

Barrett, Jeffrey C. ^{[1
]}

Sandford, Richard N. ^{[2
]}

Anderson, Carl A. ^{[1
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge, England

[2] Univ Cambridge, Acad Dept Med Genet, Cambridge, England

[3] Natl Hlth Serv NHS Fdn Trust, Cambridge Univ Hosp, Dept Hepatol, Cambridge, England

[4] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[5] Newcastle Univ, Sch Med, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[6] Kings Coll Hosp NHS Fdn Trust, Inst Liver Studies, London, England

[7] Queen Elizabeth Hosp, Liver Unit, Birmingham B15 2TH, W Midlands, England

[8] Royal Infirm Edinburgh NHS Trust, Scottish Liver Transplant Unit, Edinburgh, Midlothian, Scotland

[9] UCL, Sch Med, Hepatol Dept, London W1N 8AA, England

[10] St James Univ Hosp, Liver Unit, Leeds, W Yorkshire, England

来源：

NATURE GENETICS | 2012年 / 44卷 / 10期

基金：

英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; GENOTYPE-CALLING ALGORITHM; CLASSICAL HLA ALLELES; CLASS-II ALLELES; COMMON; RISK; RARE; POLYMORPHISMS; VARIANTS; CELLS;

D O I：

10.1038/ng.2395

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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; r(2) > 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 (r(2) > 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.

引用

页码：1137 / +

页数：7

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