Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Sun Gou Ji; Brian D. Juran; Sören Mucha; Trine Folseraas; Luke Jostins; Espen Melum; Natsuhiko Kumasaka; Elizabeth J. Atkinson; Erik M. Schlicht; Jimmy Z. Liu; Tejas Shah; Javier Gutierrez-Achury; Kirsten M. Boberg; Annika Bergquist; Severine Vermeire; Bertus Eksteen; Peter R. Durie; Martti Farkkila; Tobias Müller; Christoph Schramm; Martina Sterneck; Tobias J. Weismüller; Daniel N. Gotthardt; David Ellinghaus; Felix Braun; Andreas Teufel; Mattias Laudes; Wolfgang Lieb; Gunnar Jacobs; Ulrich Beuers; Rinse K. Weersma; Cisca Wijmenga; Hanns Ulrich Marschall; Piotr Milkiewicz; Albert Pares; Kimmo Kontula; Olivier Chazouillères; Pietro Invernizzi; Elizabeth Goode; Kelly Spiess; Carmel Moore; Jennifer Sambrook; Willem H. Ouwehand; David J. Roberts; John Danesh; Annarosa Floreani; Aliya F. Gulamhusein; John E. Eaton; Stefan Schreiber; Catalina Coltescu; Christopher L. Bowlus; Velimir A. Luketic; Joseph A. Odin; Kapil B. Chopra; Kris V. Kowdley; Naga Chalasani; Michael P. Manns; Brijesh Srivastava; George Mells; Richard N. Sandford; Graeme Alexander; Daniel J. Gaffney; Roger W. Chapman; Gideon M. Hirschfield; Mariza De Andrade; Simon M. Rushbrook; Andre Franke; Tom H. Karlsen; Konstantinos N. Lazaridis; Carl A. Anderson

doi:10.1038/ng.3745

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Sun Gou Ji, Brian D. Juran, Sören Mucha, Trine Folseraas, Luke Jostins, Espen Melum, Natsuhiko Kumasaka, Elizabeth J. Atkinson, Erik M. Schlicht, Jimmy Z. Liu, Tejas Shah, Javier Gutierrez-Achury, Kirsten M. Boberg, Annika Bergquist, Severine Vermeire, Bertus Eksteen, Peter R. Durie, Martti Farkkila, Tobias Müller, Christoph SchrammMartina Sterneck, Tobias J. Weismüller, Daniel N. Gotthardt, David Ellinghaus, Felix Braun, Andreas Teufel, Mattias Laudes, Wolfgang Lieb, Gunnar Jacobs, Ulrich Beuers, Rinse K. Weersma, Cisca Wijmenga, Hanns Ulrich Marschall, Piotr Milkiewicz, Albert Pares, Kimmo Kontula, Olivier Chazouillères, Pietro Invernizzi, Elizabeth Goode, Kelly Spiess, Carmel Moore, Jennifer Sambrook, Willem H. Ouwehand, David J. Roberts, John Danesh, Annarosa Floreani, Aliya F. Gulamhusein, John E. Eaton, Stefan Schreiber, Catalina Coltescu, Christopher L. Bowlus, Velimir A. Luketic, Joseph A. Odin, Kapil B. Chopra, Kris V. Kowdley, Naga Chalasani, Michael P. Manns, Brijesh Srivastava, George Mells, Richard N. Sandford, Graeme Alexander, Daniel J. Gaffney, Roger W. Chapman, Gideon M. Hirschfield, Mariza De Andrade, Simon M. Rushbrook, Andre Franke, Tom H. Karlsen, Konstantinos N. Lazaridis, Carl A. Anderson

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Abstract

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; â 1/475% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r G) between PSC and ulcerative colitis (UC) (r G = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r G = 0.04) (P = 2.55 × 10^-15). UC and CD were genetically more similar to each other (r G = 0.56) than either was to PSC (P < 1.0 × 10^-15). Our study represents a substantial advance in understanding of the genetics of PSC.

Original language	English (US)
Pages (from-to)	269-273
Number of pages	5
Journal	Nature Genetics
Volume	49
Issue number	2
DOIs	https://doi.org/10.1038/ng.3745
State	Published - Jan 31 2017

ASJC Scopus subject areas

Genetics

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Ji, S. G., Juran, B. D., Mucha, S., Folseraas, T., Jostins, L., Melum, E., Kumasaka, N., Atkinson, E. J., Schlicht, E. M., Liu, J. Z., Shah, T., Gutierrez-Achury, J., Boberg, K. M., Bergquist, A., Vermeire, S., Eksteen, B., Durie, P. R., Farkkila, M., Müller, T., ... Anderson, C. A. (2017). Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nature Genetics, 49(2), 269-273. https://doi.org/10.1038/ng.3745

Ji, SG, Juran, BD, Mucha, S, Folseraas, T, Jostins, L, Melum, E, Kumasaka, N, Atkinson, EJ, Schlicht, EM, Liu, JZ, Shah, T, Gutierrez-Achury, J, Boberg, KM, Bergquist, A, Vermeire, S, Eksteen, B, Durie, PR, Farkkila, M, Müller, T, Schramm, C, Sterneck, M, Weismüller, TJ, Gotthardt, DN, Ellinghaus, D, Braun, F, Teufel, A, Laudes, M, Lieb, W, Jacobs, G, Beuers, U, Weersma, RK, Wijmenga, C, Marschall, HU, Milkiewicz, P, Pares, A, Kontula, K, Chazouillères, O, Invernizzi, P, Goode, E, Spiess, K, Moore, C, Sambrook, J, Ouwehand, WH, Roberts, DJ, Danesh, J, Floreani, A, Gulamhusein, AF, Eaton, JE, Schreiber, S, Coltescu, C, Bowlus, CL, Luketic, VA, Odin, JA, Chopra, KB, Kowdley, KV, Chalasani, N, Manns, MP, Srivastava, B, Mells, G, Sandford, RN, Alexander, G, Gaffney, DJ, Chapman, RW, Hirschfield, GM, De Andrade, M, Rushbrook, SM, Franke, A, Karlsen, TH, Lazaridis, KN & Anderson, CA 2017, 'Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease', Nature Genetics, vol. 49, no. 2, pp. 269-273. https://doi.org/10.1038/ng.3745

@article{b0ec7845c24e47788046a15c6210b59a,

title = "Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease",

abstract = "Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; {\^a} 1/475% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r G) between PSC and ulcerative colitis (UC) (r G = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r G = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (r G = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.",

author = "Ji, {Sun Gou} and Juran, {Brian D.} and S{\"o}ren Mucha and Trine Folseraas and Luke Jostins and Espen Melum and Natsuhiko Kumasaka and Atkinson, {Elizabeth J.} and Schlicht, {Erik M.} and Liu, {Jimmy Z.} and Tejas Shah and Javier Gutierrez-Achury and Boberg, {Kirsten M.} and Annika Bergquist and Severine Vermeire and Bertus Eksteen and Durie, {Peter R.} and Martti Farkkila and Tobias M{\"u}ller and Christoph Schramm and Martina Sterneck and Weism{\"u}ller, {Tobias J.} and Gotthardt, {Daniel N.} and David Ellinghaus and Felix Braun and Andreas Teufel and Mattias Laudes and Wolfgang Lieb and Gunnar Jacobs and Ulrich Beuers and Weersma, {Rinse K.} and Cisca Wijmenga and Marschall, {Hanns Ulrich} and Piotr Milkiewicz and Albert Pares and Kimmo Kontula and Olivier Chazouill{\`e}res and Pietro Invernizzi and Elizabeth Goode and Kelly Spiess and Carmel Moore and Jennifer Sambrook and Ouwehand, {Willem H.} and Roberts, {David J.} and John Danesh and Annarosa Floreani and Gulamhusein, {Aliya F.} and Eaton, {John E.} and Stefan Schreiber and Catalina Coltescu and Bowlus, {Christopher L.} and Luketic, {Velimir A.} and Odin, {Joseph A.} and Chopra, {Kapil B.} and Kowdley, {Kris V.} and Naga Chalasani and Manns, {Michael P.} and Brijesh Srivastava and George Mells and Sandford, {Richard N.} and Graeme Alexander and Gaffney, {Daniel J.} and Chapman, {Roger W.} and Hirschfield, {Gideon M.} and {De Andrade}, Mariza and Rushbrook, {Simon M.} and Andre Franke and Karlsen, {Tom H.} and Lazaridis, {Konstantinos N.} and Anderson, {Carl A.}",

note = "Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature.",

year = "2017",

month = jan,

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doi = "10.1038/ng.3745",

language = "English (US)",

volume = "49",

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AU - Ji, Sun Gou

AU - Juran, Brian D.

AU - Mucha, Sören

AU - Folseraas, Trine

AU - Jostins, Luke

AU - Melum, Espen

AU - Kumasaka, Natsuhiko

AU - Atkinson, Elizabeth J.

AU - Schlicht, Erik M.

AU - Liu, Jimmy Z.

AU - Shah, Tejas

AU - Gutierrez-Achury, Javier

AU - Boberg, Kirsten M.

AU - Bergquist, Annika

AU - Vermeire, Severine

AU - Eksteen, Bertus

AU - Durie, Peter R.

AU - Farkkila, Martti

AU - Müller, Tobias

AU - Schramm, Christoph

AU - Sterneck, Martina

AU - Weismüller, Tobias J.

AU - Gotthardt, Daniel N.

AU - Ellinghaus, David

AU - Braun, Felix

AU - Teufel, Andreas

AU - Laudes, Mattias

AU - Lieb, Wolfgang

AU - Jacobs, Gunnar

AU - Beuers, Ulrich

AU - Weersma, Rinse K.

AU - Wijmenga, Cisca

AU - Marschall, Hanns Ulrich

AU - Milkiewicz, Piotr

AU - Pares, Albert

AU - Kontula, Kimmo

AU - Chazouillères, Olivier

AU - Invernizzi, Pietro

AU - Goode, Elizabeth

AU - Spiess, Kelly

AU - Moore, Carmel

AU - Sambrook, Jennifer

AU - Ouwehand, Willem H.

AU - Roberts, David J.

AU - Danesh, John

AU - Floreani, Annarosa

AU - Gulamhusein, Aliya F.

AU - Eaton, John E.

AU - Schreiber, Stefan

AU - Coltescu, Catalina

AU - Bowlus, Christopher L.

AU - Luketic, Velimir A.

AU - Odin, Joseph A.

AU - Chopra, Kapil B.

AU - Kowdley, Kris V.

AU - Chalasani, Naga

AU - Manns, Michael P.

AU - Srivastava, Brijesh

AU - Mells, George

AU - Sandford, Richard N.

AU - Alexander, Graeme

AU - Gaffney, Daniel J.

AU - Chapman, Roger W.

AU - Hirschfield, Gideon M.

AU - De Andrade, Mariza

AU - Rushbrook, Simon M.

AU - Franke, Andre

AU - Karlsen, Tom H.

AU - Lazaridis, Konstantinos N.

AU - Anderson, Carl A.

PY - 2017/1/31

Y1 - 2017/1/31

N2 - Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; â 1/475% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r G) between PSC and ulcerative colitis (UC) (r G = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r G = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (r G = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.

AB - Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; â 1/475% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r G) between PSC and ulcerative colitis (UC) (r G = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r G = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (r G = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.

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Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

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