Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

被引：309

作者：

Liu, Jimmy Z. ^{[1
]}

Hov, Johannes Roksund ^{[2
,3
,4
,5
]}

Folseraas, Trine ^{[2
,3
,4
]}

Ellinghaus, Eva ^{[6
]}

Rushbrook, Simon M. ^{[7
,8
]}

Doncheva, Nadezhda T. ^{[9
]}

Andreassen, Ole A. ^{[4
,10
]}

Weersma, Rinse K. ^{[11
,12
]}

Weismueller, Tobias J. ^{[13
,14
]}

Eksteen, Bertus ^{[15
]}

Invernizzi, Pietro ^{[16
]}

Hirschfield, Gideon M. ^{[17
,18
]}

Gotthardt, Daniel Nils ^{[19
]}

Pares, Albert ^{[20
]}

Ellinghaus, David ^{[6
]}

Shah, Tejas ^{[1
]}

Juran, Brian D. ^{[21
]}

Milkiewicz, Piotr ^{[22
,23
]}

Rust, Christian ^{[24
]}

Schramm, Christoph ^{[25
]}

Mueller, Tobias ^{[26
]}

Srivastava, Brijesh ^{[27
]}

Dalekos, Georgios ^{[28
,29
]}

Noethen, Markus M. ^{[30
,31
]}

Herms, Stefan ^{[30
,31
]}

Winkelmann, Juliane ^{[32
,33
,34
]}

Mitrovic, Mitja ^{[12
,35
]}

Braun, Felix ^{[36
]}

Ponsioen, Cyriel Y. ^{[37
]}

Croucher, Peter J. P. ^{[38
]}

Sterneck, Martina ^{[39
]}

Teufel, Andreas ^{[40
]}

Mason, Andrew L. ^{[41
]}

Saarela, Janna ^{[42
]}

Leppa, Virpi ^{[43
,44
]}

Dorfman, Ruslan ^{[45
]}

Alvaro, Domenico ^{[46
]}

Floreani, Annarosa ^{[47
]}

Onengut-Gumuscu, Suna ^{[48
,49
]}

Rich, Stephen S. ^{[50
,51
]}

Thompson, Wesley K. ^{[52
]}

Schork, Andrew J. ^{[53
]}

Naess, Sigrid ^{[2
,3
,4
]}

Thomsen, Ingo ^{[6
]}

Mayr, Gabriele ^{[9
]}

Koenig, Inke R. ^{[54
]}

Hveem, Kristian ^{[55
]}

Cleynen, Isabelle ^{[1
,56
]}

Gutierrez-Achury, Javier ^{[12
,35
]}

Ricano-Ponce, Isis ^{[12
,35
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge, England

[2] Oslo Univ Hosp, Rikshosp, Div Canc Med Surg & Transplantat, Norwegian PSC Res Ctr,Dept Transplantat Med, Oslo, Norway

[3] Oslo Univ Hosp, Rikshosp, Internal Med Res Inst, KG Jebsen Inflammat Res Ctr, Oslo, Norway

[4] Univ Oslo, Inst Clin Med, Oslo, Norway

[5] Oslo Univ Hosp, Rikshosp, Div Canc Med Surg & Transplantat, Sect Gastroenterol,Dept Transplantat Med, Oslo, Norway

[6] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[7] Dept Gastroenterol & Hepatol, Norfolk, VA USA

[8] Univ Hosp Natl Hlth Serv NHS Trust, Norwich, Norfolk, England

[9] Max Planck Inst Informat, D-66123 Saarbrucken, Germany

[10] Oslo Univ Hosp, Div Mental Hlth & Addict, KG Jebsen Ctr Psychosis Res, Oslo, Norway

[11] Univ Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands

[12] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands

[13] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany

[14] Hannover Med Sch, Integrated Res & Treatment Ctr Transplantat IFB T, Hannover, Germany

[15] Univ Calgary, Dept Med, Snyder Inst Chron Dis, Calgary, AB, Canada

[16] Humanitas Clin & Res Ctr, Ctr Autoimmune Liver Dis, Rozzano, Italy

[17] Univ Toronto, Dept Med, Div Gastroenterol, Toronto, ON, Canada

[18] NIHR, Liver Res Ctr, Biomed Res Unit, Birmingham, W Midlands, England

[19] Univ Heidelberg Hosp, Dept Med, Heidelberg, Germany

[20] Univ Barcelona, IDIBAPS, CIBERehd, Liver Unit,Hosp Clin, Barcelona, Spain

[21] Mayo Clin, Coll Med, Ctr Basic Res Digest Dis, Div Gastroenterol & Hepatol, Rochester, MN USA

[22] Pomeranian Med Univ, Liver Unit, Szczecin, Poland

[23] Pomeranian Med Univ, Liver Res Labs, Szczecin, Poland

[24] Univ Munich, Dept Med 2, Munich, Germany

[25] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany

[26] Charite, Dept Internal Med Hepatol & Gastroenterol, D-13353 Berlin, Germany

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

[28] Univ Thessaly, Sch Med, Dept Med, Larisa, Greece

[29] Univ Thessaly, Sch Med, Larisa, Greece

[30] Univ Bonn, Inst Human Genet, Bonn, Germany

[31] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany

[32] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany

[33] Tech Univ Munich, Dept Neurol, D-80290 Munich, Germany

[34] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[35] Univ Groningen, Dept Genet, Groningen, Netherlands

[36] Univ Med Ctr Schleswig Holstein, Dept Gen Visceral Thorac Transplantat & Pediat Su, Kiel, Germany

[37] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

[38] Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA

[39] Univ Med Ctr Hamburg Eppendorf, Dept Hepatobiliary Surg & Transplantat, Hamburg, Germany

[40] Johannes Gutenberg Univ Mainz, Dept Med 1, Mainz, Germany

[41] Univ Alberta, Div Gastroenterol & Hepatol, Edmonton, AB, Canada

[42] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[43] Univ Helsinki, FIMM, Publ Hlth Genom Unit, Helsinki, Finland

[44] Natl Inst Hlth & Welf, Helsinki, Finland

[45] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[46] Univ Roma La Sapienza, Dept Clin Med, Div Gastroenterol, Rome, Italy

[47] Univ Padua, Dept Surg Oncol & Gastroenterol Sci, Padua, Italy

[48] Univ Virginia, Div Endocrinol & Metab, Ctr Publ Hlth Genom, Charlottesville, VA USA

[49] Univ Virginia, Dept Internal Med, Div Endocrinol & Metab, Charlottesville, VA USA

[50] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 06期

基金：

英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; FALSE DISCOVERY RATE; HISTONE DEACETYLASE; SUSCEPTIBILITY LOCI; ULCERATIVE-COLITIS; NATURAL-HISTORY; BOWEL-DISEASE; GENETIC RISK; MIXED-MODEL; HLA;

D O I：

10.1038/ng.2616

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation(1-3). We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip(4). We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

引用

页码：670 / +

页数：8

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