Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Luke Jostins, Stephan Ripke, Rinse K. Weersma, Richard H. Duerr, Dermot P. McGovern, Ken Y. Hui, James C. Lee, L. Philip Schumm, Yashoda Sharma, Carl A. Anderson, Jonah Essers, Mitja Mitrovic, Kaida Ning, Isabelle Cleynen, Emilie Theatre, Sarah L. Spain, Soumya Raychaudhuri, Philippe Goyette, Zhi Wei, Clara Abraham & 86 others Jean Paul Achkar, Tariq Ahmad, Leila Amininejad, Ashwin N. Ananthakrishnan, Vibeke Andersen, Jane M. Andrews, Leonard Baidoo, Tobias Balschun, Peter A. Bampton, Alain Bitton, Gabrielle Boucher, Stephan Brand, Carsten Büning, Ariella Cohain, Sven Cichon, Mauro D'Amato, Dirk De Jong, Kathy L. Devaney, Marla Dubinsky, Cathryn Edwards, David Ellinghaus, Lynnette R. Ferguson, Denis Franchimont, Karin Fransen, Richard Gearry, Michel Georges, Christian Gieger, Jürgen Glas, Talin Haritunians, Ailsa Hart, Chris Hawkey, Matija Hedl, Xinli Hu, Tom H. Karlsen, Limas Kupcinskas, Subra Kugathasan, Anna Latiano, Debby Laukens, Ian C. Lawrance, Charlie W. Lees, Edouard Louis, Gillian Mahy, John Mansfield, Angharad R. Morgan, Craig Mowat, William Newman, Orazio Palmieri, Cyriel Y. Ponsioen, Uros Potocnik, Natalie J. Prescott, Miguel Regueiro, Jerome I. Rotter, Richard K. Russell, Jeremy D. Sanderson, Miquel Sans, Jack Satsangi, Stefan Schreiber, Lisa A. Simms, Jurgita Sventoraityte, Stephan R. Targan, Kent D. Taylor, Mark Tremelling, Hein W. Verspaget, Martine De Vos, Cisca Wijmenga, David C. Wilson, Juliane Winkelmann, Ramnik J. Xavier, Sebastian Zeissig, Bin Zhang, Clarence K. Zhang, Hongyu Zhao, Mark S. Silverberg, Vito Annese, Hakon Hakonarson, Steven R. Brant, Graham Radford-Smith, Christopher G. Mathew, John D. Rioux, Eric E. Schadt, Mark J. Daly, Andre Franke, Miles Parkes, Severine Vermeire, Jeffrey C. Barrett, Lisa Datta

Research output: Contribution to journalArticle

Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Original languageEnglish (US)
Pages (from-to)119-124
Number of pages6
JournalNature
Volume491
Issue number7422
DOIs
StatePublished - Nov 1 2012

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Inflammatory Bowel Diseases
Genome-Wide Association Study
Ulcerative Colitis
Crohn Disease
Meta-Analysis
Alleles
Phenotype
Ankylosing Spondylitis
Immune System Diseases
Autophagy
Mycobacterium
Psoriasis
Population
History
Genome
Gene Expression
Infection

ASJC Scopus subject areas

  • General

Cite this

Jostins, L., Ripke, S., Weersma, R. K., Duerr, R. H., McGovern, D. P., Hui, K. Y., ... Datta, L. (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119-124. https://doi.org/10.1038/nature11582

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. / Jostins, Luke; Ripke, Stephan; Weersma, Rinse K.; Duerr, Richard H.; McGovern, Dermot P.; Hui, Ken Y.; Lee, James C.; Philip Schumm, L.; Sharma, Yashoda; Anderson, Carl A.; Essers, Jonah; Mitrovic, Mitja; Ning, Kaida; Cleynen, Isabelle; Theatre, Emilie; Spain, Sarah L.; Raychaudhuri, Soumya; Goyette, Philippe; Wei, Zhi; Abraham, Clara; Achkar, Jean Paul; Ahmad, Tariq; Amininejad, Leila; Ananthakrishnan, Ashwin N.; Andersen, Vibeke; Andrews, Jane M.; Baidoo, Leonard; Balschun, Tobias; Bampton, Peter A.; Bitton, Alain; Boucher, Gabrielle; Brand, Stephan; Büning, Carsten; Cohain, Ariella; Cichon, Sven; D'Amato, Mauro; De Jong, Dirk; Devaney, Kathy L.; Dubinsky, Marla; Edwards, Cathryn; Ellinghaus, David; Ferguson, Lynnette R.; Franchimont, Denis; Fransen, Karin; Gearry, Richard; Georges, Michel; Gieger, Christian; Glas, Jürgen; Haritunians, Talin; Hart, Ailsa; Hawkey, Chris; Hedl, Matija; Hu, Xinli; Karlsen, Tom H.; Kupcinskas, Limas; Kugathasan, Subra; Latiano, Anna; Laukens, Debby; Lawrance, Ian C.; Lees, Charlie W.; Louis, Edouard; Mahy, Gillian; Mansfield, John; Morgan, Angharad R.; Mowat, Craig; Newman, William; Palmieri, Orazio; Ponsioen, Cyriel Y.; Potocnik, Uros; Prescott, Natalie J.; Regueiro, Miguel; Rotter, Jerome I.; Russell, Richard K.; Sanderson, Jeremy D.; Sans, Miquel; Satsangi, Jack; Schreiber, Stefan; Simms, Lisa A.; Sventoraityte, Jurgita; Targan, Stephan R.; Taylor, Kent D.; Tremelling, Mark; Verspaget, Hein W.; De Vos, Martine; Wijmenga, Cisca; Wilson, David C.; Winkelmann, Juliane; Xavier, Ramnik J.; Zeissig, Sebastian; Zhang, Bin; Zhang, Clarence K.; Zhao, Hongyu; Silverberg, Mark S.; Annese, Vito; Hakonarson, Hakon; Brant, Steven R.; Radford-Smith, Graham; Mathew, Christopher G.; Rioux, John D.; Schadt, Eric E.; Daly, Mark J.; Franke, Andre; Parkes, Miles; Vermeire, Severine; Barrett, Jeffrey C.; Datta, Lisa.

In: Nature, Vol. 491, No. 7422, 01.11.2012, p. 119-124.

Research output: Contribution to journalArticle

Jostins, L, Ripke, S, Weersma, RK, Duerr, RH, McGovern, DP, Hui, KY, Lee, JC, Philip Schumm, L, Sharma, Y, Anderson, CA, Essers, J, Mitrovic, M, Ning, K, Cleynen, I, Theatre, E, Spain, SL, Raychaudhuri, S, Goyette, P, Wei, Z, Abraham, C, Achkar, JP, Ahmad, T, Amininejad, L, Ananthakrishnan, AN, Andersen, V, Andrews, JM, Baidoo, L, Balschun, T, Bampton, PA, Bitton, A, Boucher, G, Brand, S, Büning, C, Cohain, A, Cichon, S, D'Amato, M, De Jong, D, Devaney, KL, Dubinsky, M, Edwards, C, Ellinghaus, D, Ferguson, LR, Franchimont, D, Fransen, K, Gearry, R, Georges, M, Gieger, C, Glas, J, Haritunians, T, Hart, A, Hawkey, C, Hedl, M, Hu, X, Karlsen, TH, Kupcinskas, L, Kugathasan, S, Latiano, A, Laukens, D, Lawrance, IC, Lees, CW, Louis, E, Mahy, G, Mansfield, J, Morgan, AR, Mowat, C, Newman, W, Palmieri, O, Ponsioen, CY, Potocnik, U, Prescott, NJ, Regueiro, M, Rotter, JI, Russell, RK, Sanderson, JD, Sans, M, Satsangi, J, Schreiber, S, Simms, LA, Sventoraityte, J, Targan, SR, Taylor, KD, Tremelling, M, Verspaget, HW, De Vos, M, Wijmenga, C, Wilson, DC, Winkelmann, J, Xavier, RJ, Zeissig, S, Zhang, B, Zhang, CK, Zhao, H, Silverberg, MS, Annese, V, Hakonarson, H, Brant, SR, Radford-Smith, G, Mathew, CG, Rioux, JD, Schadt, EE, Daly, MJ, Franke, A, Parkes, M, Vermeire, S, Barrett, JC & Datta, L 2012, 'Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease', Nature, vol. 491, no. 7422, pp. 119-124. https://doi.org/10.1038/nature11582
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119-124. https://doi.org/10.1038/nature11582
Jostins, Luke ; Ripke, Stephan ; Weersma, Rinse K. ; Duerr, Richard H. ; McGovern, Dermot P. ; Hui, Ken Y. ; Lee, James C. ; Philip Schumm, L. ; Sharma, Yashoda ; Anderson, Carl A. ; Essers, Jonah ; Mitrovic, Mitja ; Ning, Kaida ; Cleynen, Isabelle ; Theatre, Emilie ; Spain, Sarah L. ; Raychaudhuri, Soumya ; Goyette, Philippe ; Wei, Zhi ; Abraham, Clara ; Achkar, Jean Paul ; Ahmad, Tariq ; Amininejad, Leila ; Ananthakrishnan, Ashwin N. ; Andersen, Vibeke ; Andrews, Jane M. ; Baidoo, Leonard ; Balschun, Tobias ; Bampton, Peter A. ; Bitton, Alain ; Boucher, Gabrielle ; Brand, Stephan ; Büning, Carsten ; Cohain, Ariella ; Cichon, Sven ; D'Amato, Mauro ; De Jong, Dirk ; Devaney, Kathy L. ; Dubinsky, Marla ; Edwards, Cathryn ; Ellinghaus, David ; Ferguson, Lynnette R. ; Franchimont, Denis ; Fransen, Karin ; Gearry, Richard ; Georges, Michel ; Gieger, Christian ; Glas, Jürgen ; Haritunians, Talin ; Hart, Ailsa ; Hawkey, Chris ; Hedl, Matija ; Hu, Xinli ; Karlsen, Tom H. ; Kupcinskas, Limas ; Kugathasan, Subra ; Latiano, Anna ; Laukens, Debby ; Lawrance, Ian C. ; Lees, Charlie W. ; Louis, Edouard ; Mahy, Gillian ; Mansfield, John ; Morgan, Angharad R. ; Mowat, Craig ; Newman, William ; Palmieri, Orazio ; Ponsioen, Cyriel Y. ; Potocnik, Uros ; Prescott, Natalie J. ; Regueiro, Miguel ; Rotter, Jerome I. ; Russell, Richard K. ; Sanderson, Jeremy D. ; Sans, Miquel ; Satsangi, Jack ; Schreiber, Stefan ; Simms, Lisa A. ; Sventoraityte, Jurgita ; Targan, Stephan R. ; Taylor, Kent D. ; Tremelling, Mark ; Verspaget, Hein W. ; De Vos, Martine ; Wijmenga, Cisca ; Wilson, David C. ; Winkelmann, Juliane ; Xavier, Ramnik J. ; Zeissig, Sebastian ; Zhang, Bin ; Zhang, Clarence K. ; Zhao, Hongyu ; Silverberg, Mark S. ; Annese, Vito ; Hakonarson, Hakon ; Brant, Steven R. ; Radford-Smith, Graham ; Mathew, Christopher G. ; Rioux, John D. ; Schadt, Eric E. ; Daly, Mark J. ; Franke, Andre ; Parkes, Miles ; Vermeire, Severine ; Barrett, Jeffrey C. ; Datta, Lisa. / Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. In: Nature. 2012 ; Vol. 491, No. 7422. pp. 119-124.
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AU - Hui, Ken Y.

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AU - Mitrovic, Mitja

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AU - Spain, Sarah L.

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AU - Bitton, Alain

AU - Boucher, Gabrielle

AU - Brand, Stephan

AU - Büning, Carsten

AU - Cohain, Ariella

AU - Cichon, Sven

AU - D'Amato, Mauro

AU - De Jong, Dirk

AU - Devaney, Kathy L.

AU - Dubinsky, Marla

AU - Edwards, Cathryn

AU - Ellinghaus, David

AU - Ferguson, Lynnette R.

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AU - Gearry, Richard

AU - Georges, Michel

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AU - Glas, Jürgen

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AU - Kugathasan, Subra

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AU - Lawrance, Ian C.

AU - Lees, Charlie W.

AU - Louis, Edouard

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AU - Mansfield, John

AU - Morgan, Angharad R.

AU - Mowat, Craig

AU - Newman, William

AU - Palmieri, Orazio

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AU - Potocnik, Uros

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AU - Sans, Miquel

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AU - Wijmenga, Cisca

AU - Wilson, David C.

AU - Winkelmann, Juliane

AU - Xavier, Ramnik J.

AU - Zeissig, Sebastian

AU - Zhang, Bin

AU - Zhang, Clarence K.

AU - Zhao, Hongyu

AU - Silverberg, Mark S.

AU - Annese, Vito

AU - Hakonarson, Hakon

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AU - Radford-Smith, Graham

AU - Mathew, Christopher G.

AU - Rioux, John D.

AU - Schadt, Eric E.

AU - Daly, Mark J.

AU - Franke, Andre

AU - Parkes, Miles

AU - Vermeire, Severine

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AB - Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

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