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

Jimmy Z Liu; Johannes Roksund Hov; Trine Folseraas; Eva Ellinghaus; Simon M Rushbrook; Nadezhda T Doncheva; Ole A Andreassen; Rinse K Weersma; Tobias J Weismüller; Bertus Eksteen; Pietro Invernizzi; Gideon M Hirschfield; Daniel Nils Gotthardt; Albert Pares; David Ellinghaus; Tejas Shah; Brian D Juran; Piotr Milkiewicz; Christian Rust; Christoph Schramm; Tobias Müller; Brijesh Srivastava; Georgios Dalekos; Markus M Nöthen; Stefan Herms; Juliane Winkelmann; Mitja Mitrovic; Felix Braun; Cyriel Y Ponsioen; Peter J P Croucher; Martina Sterneck; Andreas Teufel; Andrew L Mason; Janna Saarela; Virpi Leppa; Ruslan Dorfman; Domenico Alvaro; Annarosa Floreani; Suna Onengut-Gumuscu; Stephen S Rich; Wesley K Thompson; Andrew J Schork; Sigrid Næss; Ingo Thomsen; Gabriele Mayr; Inke R König; Kristian Hveem; Isabelle Cleynen; Javier Gutierrez-Achury; Isis Ricaño-Ponce; UK-PSCSC Consortium

doi:10.1038/ng.2616

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

Jimmy Z Liu, Johannes Roksund Hov, Trine Folseraas, Eva Ellinghaus, Simon M Rushbrook, Nadezhda T Doncheva, Ole A Andreassen, Rinse K Weersma, Tobias J Weismüller, Bertus Eksteen, Pietro Invernizzi, Gideon M Hirschfield, Daniel Nils Gotthardt, Albert Pares, David Ellinghaus, Tejas Shah, Brian D Juran, Piotr Milkiewicz, Christian Rust, Christoph SchrammTobias Müller, Brijesh Srivastava, Georgios Dalekos, Markus M Nöthen, Stefan Herms, Juliane Winkelmann, Mitja Mitrovic, Felix Braun, Cyriel Y Ponsioen, Peter J P Croucher, Martina Sterneck, Andreas Teufel, Andrew L Mason, Janna Saarela, Virpi Leppa, Ruslan Dorfman, Domenico Alvaro, Annarosa Floreani, Suna Onengut-Gumuscu, Stephen S Rich, Wesley K Thompson, Andrew J Schork, Sigrid Næss, Ingo Thomsen, Gabriele Mayr, Inke R König, Kristian Hveem, Isabelle Cleynen, Javier Gutierrez-Achury, Isis Ricaño-Ponce, UK-PSCSC Consortium

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

233 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	670-5
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	6
DOIs	https://doi.org/10.1038/ng.2616
Publication status	Published - Jun 2013

Keywords

Case-Control Studies
Cholangitis, Sclerosing
Gene Frequency
Genetic Loci
Genetic Pleiotropy
Genome-Wide Association Study
Genotyping Techniques
Humans
Linkage Disequilibrium
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Risk Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2616

Mucosal Lymphocytes in the Pathogenesis of Primary Sclerosing Cholangitis
Eksteen, B.
Medical Research Council
1/10/07 → 31/03/13
Project: Research Councils

Cite this

Liu, J. Z., Hov, J. R., Folseraas, T., Ellinghaus, E., Rushbrook, S. M., Doncheva, N. T., Andreassen, O. A., Weersma, R. K., Weismüller, T. J., Eksteen, B., Invernizzi, P., Hirschfield, G. M., Gotthardt, D. N., Pares, A., Ellinghaus, D., Shah, T., Juran, B. D., Milkiewicz, P., Rust, C., ... UK-PSCSC Consortium (2013). Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nature Genetics, 45(6), 670-5. https://doi.org/10.1038/ng.2616

@article{1c54d5ccbc7a40d4bc6ccdf59c479e76,

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

abstract = "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.",

keywords = "Case-Control Studies, Cholangitis, Sclerosing, Gene Frequency, Genetic Loci, Genetic Pleiotropy, Genome-Wide Association Study, Genotyping Techniques, Humans, Linkage Disequilibrium, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Risk Factors",

author = "Liu, {Jimmy Z} and Hov, {Johannes Roksund} and Trine Folseraas and Eva Ellinghaus and Rushbrook, {Simon M} and Doncheva, {Nadezhda T} and Andreassen, {Ole A} and Weersma, {Rinse K} and Weism{\"u}ller, {Tobias J} and Bertus Eksteen and Pietro Invernizzi and Hirschfield, {Gideon M} and Gotthardt, {Daniel Nils} and Albert Pares and David Ellinghaus and Tejas Shah and Juran, {Brian D} and Piotr Milkiewicz and Christian Rust and Christoph Schramm and Tobias M{\"u}ller and Brijesh Srivastava and Georgios Dalekos and N{\"o}then, {Markus M} and Stefan Herms and Juliane Winkelmann and Mitja Mitrovic and Felix Braun and Ponsioen, {Cyriel Y} and Croucher, {Peter J P} and Martina Sterneck and Andreas Teufel and Mason, {Andrew L} and Janna Saarela and Virpi Leppa and Ruslan Dorfman and Domenico Alvaro and Annarosa Floreani and Suna Onengut-Gumuscu and Rich, {Stephen S} and Thompson, {Wesley K} and Schork, {Andrew J} and Sigrid N{\ae}ss and Ingo Thomsen and Gabriele Mayr and K{\"o}nig, {Inke R} and Kristian Hveem and Isabelle Cleynen and Javier Gutierrez-Achury and Isis Rica{\~n}o-Ponce and {UK-PSCSC Consortium}",

year = "2013",

month = jun,

doi = "10.1038/ng.2616",

language = "English",

volume = "45",

pages = "670--5",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

Liu, JZ, Hov, JR, Folseraas, T, Ellinghaus, E, Rushbrook, SM, Doncheva, NT, Andreassen, OA, Weersma, RK, Weismüller, TJ, Eksteen, B, Invernizzi, P, Hirschfield, GM, Gotthardt, DN, Pares, A, Ellinghaus, D, Shah, T, Juran, BD, Milkiewicz, P, Rust, C, Schramm, C, Müller, T, Srivastava, B, Dalekos, G, Nöthen, MM, Herms, S, Winkelmann, J, Mitrovic, M, Braun, F, Ponsioen, CY, Croucher, PJP, Sterneck, M, Teufel, A, Mason, AL, Saarela, J, Leppa, V, Dorfman, R, Alvaro, D, Floreani, A, Onengut-Gumuscu, S, Rich, SS, Thompson, WK, Schork, AJ, Næss, S, Thomsen, I, Mayr, G, König, IR, Hveem, K, Cleynen, I, Gutierrez-Achury, J, Ricaño-Ponce, I & UK-PSCSC Consortium 2013, 'Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis', Nature Genetics, vol. 45, no. 6, pp. 670-5. https://doi.org/10.1038/ng.2616

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 - UK-PSCSC Consortium

PY - 2013/6

Y1 - 2013/6

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 - Article

C2 - 23603763

SN - 1061-4036

VL - 45

SP - 670

EP - 675

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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Projects

Mucosal Lymphocytes in the Pathogenesis of Primary Sclerosing Cholangitis

Cite this