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

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)269-273
Number of pages5
JournalNature Genetics
Volume49
Issue number2
DOIs
StatePublished - Jan 31 2017

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Sclerosing Cholangitis
Genetic Loci
Genome-Wide Association Study
Inflammatory Bowel Diseases
Ulcerative Colitis
Crohn Disease
Genome
Population Control
RNA Stability
Bile Ducts
Single Nucleotide Polymorphism
Alleles

ASJC Scopus subject areas

  • Genetics

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

In: Nature Genetics, Vol. 49, No. 2, 31.01.2017, p. 269-273.

Research output: Contribution to journalArticle

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
Ji, Sun Gou ; Juran, Brian D. ; Mucha, Sören ; Folseraas, Trine ; Jostins, Luke ; Melum, Espen ; Kumasaka, Natsuhiko ; Atkinson, Elizabeth J. ; Schlicht, Erik M. ; Liu, Jimmy Z. ; Shah, Tejas ; Gutierrez-Achury, Javier ; Boberg, Kirsten M. ; Bergquist, Annika ; Vermeire, Severine ; Eksteen, Bertus ; Durie, Peter R. ; Farkkila, Martti ; Müller, Tobias ; Schramm, Christoph ; Sterneck, Martina ; Weismüller, Tobias J. ; Gotthardt, Daniel N. ; Ellinghaus, David ; Braun, Felix ; Teufel, Andreas ; Laudes, Mattias ; Lieb, Wolfgang ; Jacobs, Gunnar ; Beuers, Ulrich ; Weersma, Rinse K. ; Wijmenga, Cisca ; Marschall, Hanns Ulrich ; Milkiewicz, Piotr ; Pares, Albert ; Kontula, Kimmo ; Chazouillères, Olivier ; Invernizzi, Pietro ; Goode, Elizabeth ; Spiess, Kelly ; Moore, Carmel ; Sambrook, Jennifer ; Ouwehand, Willem H. ; Roberts, David J. ; Danesh, John ; Floreani, Annarosa ; Gulamhusein, Aliya F. ; Eaton, John E. ; Schreiber, Stefan ; Coltescu, Catalina ; Bowlus, Christopher L. ; Luketic, Velimir A. ; Odin, Joseph A. ; Chopra, Kapil B. ; Kowdley, Kris V. ; Chalasani, Naga ; Manns, Michael P. ; Srivastava, Brijesh ; Mells, George ; Sandford, Richard N. ; Alexander, Graeme ; Gaffney, Daniel J. ; Chapman, Roger W. ; Hirschfield, Gideon M. ; De Andrade, Mariza ; Rushbrook, Simon M. ; Franke, Andre ; Karlsen, Tom H. ; Lazaridis, Konstantinos N. ; Anderson, Carl A. / Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. In: Nature Genetics. 2017 ; Vol. 49, No. 2. pp. 269-273.
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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

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AU - Lieb, Wolfgang

AU - Jacobs, Gunnar

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AU - Sambrook, Jennifer

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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.

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AU - De Andrade, Mariza

AU - Rushbrook, Simon M.

AU - Franke, Andre

AU - Karlsen, Tom H.

AU - Lazaridis, Konstantinos N.

AU - Anderson, Carl A.

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