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

TY - JOUR

T1 - Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

AU - Liu, Jimmy Z

AU - Hov, Johannes Roksund

AU - Folseraas, Trine

AU - Ellinghaus, Eva

AU - Rushbrook, Simon M

AU - Doncheva, Nadezhda T

AU - Andreassen, Ole A

AU - Weersma, Rinse K

AU - Weismüller, Tobias J

AU - Eksteen, Bertus

AU - Invernizzi, Pietro

AU - Hirschfield, Gideon M

AU - Gotthardt, Daniel Nils

AU - Pares, Albert

AU - Ellinghaus, David

AU - Shah, Tejas

AU - Juran, Brian D

AU - Milkiewicz, Piotr

AU - Rust, Christian

AU - Schramm, Christoph

AU - Müller, Tobias

AU - Srivastava, Brijesh

AU - Dalekos, Georgios

AU - Nöthen, Markus M

AU - Herms, Stefan

AU - Winkelmann, Juliane

AU - Mitrovic, Mitja

AU - Braun, Felix

AU - Ponsioen, Cyriel Y

AU - Croucher, Peter J P

AU - Sterneck, Martina

AU - Teufel, Andreas

AU - Mason, Andrew L

AU - Saarela, Janna

AU - Leppa, Virpi

AU - Dorfman, Ruslan

AU - Alvaro, Domenico

AU - Floreani, Annarosa

AU - Onengut-Gumuscu, Suna

AU - Rich, Stephen S

AU - Thompson, Wesley K

AU - Schork, Andrew J

AU - Næss, Sigrid

AU - Thomsen, Ingo

AU - Mayr, Gabriele

AU - König, Inke R

AU - Hveem, Kristian

AU - Cleynen, Isabelle

AU - Gutierrez-Achury, Javier

AU - Ricaño-Ponce, Isis

AU - van Heel, David

AU - Björnsson, Einar

AU - Sandford, Richard N

AU - Durie, Peter R

AU - Melum, Espen

AU - Vatn, Morten H

AU - Silverberg, Mark S

AU - Duerr, Richard H

AU - Padyukov, Leonid

AU - Brand, Stephan

AU - Sans, Miquel

AU - Annese, Vito

AU - Achkar, Jean-Paul

AU - Boberg, Kirsten Muri

AU - Marschall, Hanns-Ulrich

AU - Chazouillères, Olivier

AU - Bowlus, Christopher L

AU - Wijmenga, Cisca

AU - Schrumpf, Erik

AU - Vermeire, Severine

AU - Albrecht, Mario

AU - Rioux, John D

AU - Alexander, Graeme

AU - Bergquist, Annika

AU - Cho, Judy

AU - Schreiber, Stefan

AU - Manns, Michael P

AU - Färkkilä, Martti

AU - Dale, Anders M

AU - Chapman, Roger W

AU - Lazaridis, Konstantinos N

AU - Franke, Andre

AU - Anderson, Carl A

AU - Karlsen, Tom H

AU - UK-PSCSC Consortium

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. 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.

AB - 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. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. 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.

KW - Case-Control Studies

KW - Cholangitis, Sclerosing

KW - Gene Frequency

KW - Genetic Loci

KW - Genetic Pleiotropy

KW - Genome-Wide Association Study

KW - Genotyping Techniques

KW - Humans

KW - Linkage Disequilibrium

KW - Oligonucleotide Array Sequence Analysis

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

U2 - 10.1038/ng.2616

DO - 10.1038/ng.2616

M3 - SCORING: Journal article

C2 - 23603763

VL - 45

SP - 670

EP - 675

JO - NAT GENET

JF - NAT GENET

SN - 1061-4036

IS - 6

ER -