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; 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; Judy H. Cho

doi:10.1038/nature11582

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 AbrahamJean 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, Judy H. Cho

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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 language	English (US)
Pages (from-to)	119-124
Number of pages	6
Journal	Nature
Volume	491
Issue number	7422
DOIs	https://doi.org/10.1038/nature11582
State	Published - Nov 1 2012

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10.1038/nature11582

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Jostins, L., Ripke, S., Weersma, R. K., Duerr, R. H., McGovern, D. P., Hui, K. Y., Lee, J. C., Schumm, L. P., Sharma, Y., Anderson, C. A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S. L., Raychaudhuri, S., Goyette, P., Wei, Z., ... Cho, J. H. (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119-124. https://doi.org/10.1038/nature11582

@article{88ab012a0b5b47618c7aacf88e41ae01,

title = "Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease",

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.",

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

year = "2012",

month = nov,

day = "1",

doi = "10.1038/nature11582",

language = "English (US)",

volume = "491",

pages = "119--124",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7422",

}

Jostins, L, Ripke, S, Weersma, RK, Duerr, RH, McGovern, DP, Hui, KY, Lee, JC, Schumm, LP, 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, Jong, DD, 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, Vos, MD, 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 & Cho, JH 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

TY - JOUR

T1 - Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

AU - Jostins, Luke

AU - Ripke, Stephan

AU - Weersma, Rinse K.

AU - Duerr, Richard H.

AU - McGovern, Dermot P.

AU - Hui, Ken Y.

AU - Lee, James C.

AU - Schumm, L. Philip

AU - Sharma, Yashoda

AU - Anderson, Carl A.

AU - Essers, Jonah

AU - Mitrovic, Mitja

AU - Ning, Kaida

AU - Cleynen, Isabelle

AU - Theatre, Emilie

AU - Spain, Sarah L.

AU - Raychaudhuri, Soumya

AU - Goyette, Philippe

AU - Wei, Zhi

AU - Abraham, Clara

AU - Achkar, Jean Paul

AU - Ahmad, Tariq

AU - Amininejad, Leila

AU - Ananthakrishnan, Ashwin N.

AU - Andersen, Vibeke

AU - Andrews, Jane M.

AU - Baidoo, Leonard

AU - Balschun, Tobias

AU - Bampton, Peter A.

AU - Bitton, Alain

AU - Boucher, Gabrielle

AU - Brand, Stephan

AU - Büning, Carsten

AU - Cohain, Ariella

AU - Cichon, Sven

AU - D’amato, Mauro

AU - Jong, Dirk De

AU - Devaney, Kathy L.

AU - Dubinsky, Marla

AU - Edwards, Cathryn

AU - Ellinghaus, David

AU - Ferguson, Lynnette R.

AU - Franchimont, Denis

AU - Fransen, Karin

AU - Gearry, Richard

AU - Georges, Michel

AU - Gieger, Christian

AU - Glas, Jürgen

AU - Haritunians, Talin

AU - Hart, Ailsa

AU - Hawkey, Chris

AU - Hedl, Matija

AU - Hu, Xinli

AU - Karlsen, Tom H.

AU - Kupcinskas, Limas

AU - Kugathasan, Subra

AU - Latiano, Anna

AU - Laukens, Debby

AU - Lawrance, Ian C.

AU - Lees, Charlie W.

AU - Louis, Edouard

AU - Mahy, Gillian

AU - Mansfield, John

AU - Morgan, Angharad R.

AU - Mowat, Craig

AU - Newman, William

AU - Palmieri, Orazio

AU - Ponsioen, Cyriel Y.

AU - Potocnik, Uros

AU - Prescott, Natalie J.

AU - Regueiro, Miguel

AU - Rotter, Jerome I.

AU - Russell, Richard K.

AU - Sanderson, Jeremy D.

AU - Sans, Miquel

AU - Satsangi, Jack

AU - Schreiber, Stefan

AU - Simms, Lisa A.

AU - Sventoraityte, Jurgita

AU - Targan, Stephan R.

AU - Taylor, Kent D.

AU - Tremelling, Mark

AU - Verspaget, Hein W.

AU - Vos, Martine De

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

AU - Brant, Steven R.

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

AU - Barrett, Jeffrey C.

AU - Cho, Judy H.

PY - 2012/11/1

Y1 - 2012/11/1

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84868336049&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868336049&partnerID=8YFLogxK

U2 - 10.1038/nature11582

DO - 10.1038/nature11582

M3 - Article

C2 - 23128233

AN - SCOPUS:84868336049

SN - 0028-0836

VL - 491

SP - 119

EP - 124

JO - Nature

JF - Nature

IS - 7422

ER -

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

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