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Nature, 1 November 2012, Volume 491

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, The International IBD Genetics Consortium (IIBDGC){, 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

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 populations1. Genome-wide association studies and subsequent meta-analyses of these two diseases2,3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy4, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. 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.

LIST OF PARTICIPANTS

Legend:       Coordinating PI     Participants

1. BE-SMART | 2. CEDAR-UC | 3. COMBINED THERAPY OF BIOLOGICALS AND NEW ORAL DRUGS. | 4. DETECT | 5. DNA BANKING | 6. GENGISCAN | 7. HELP-AID | 8. I-CARE | 9. IMMUNIZATION | 10. LOVE | 11. PACIFIC | 12. PEDIATRIC | 13. SPARE
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- - x x x x
Leila Amininejad x x x
Saskia Appelmans
Filip Baert x x x x x x
Thomas Billiet
Patrick Bontems
Peter Bossuyt x x x x x x
Guillaume Burnet
Peter Burvenich
Philippe Caenepeel
Olivier Cajot
Christophe Claessens x
Jean-Charles Coche
Jean-Louis Coenegrachts
Arnaud Colard x
Filip Couturier
Anneline Cremer x x
Cléo Croonen
Francois D'Heygere x
Steven De Coninck
Elisabeth De Greef x
Marc De Maeyer
Marc De Reuck
Elodie De Ruyck
Nicolas de Suray
Martine De Vos x x x x
Benedicte De Vroey
Stefan Delen
Marie-Armelle Denis
Pieter Dewint x x
Olivier Dewit x x x
Sophie Dewit x x
Joris Dutre
Marc Etienne
Marc Ferrante x x x x x
René Fiasse
Fernand Fontaine x x
Denis Franchimont x x x x x x
Pieter Hindryckx x
Ilse Hoffman
Evelien Humblet x
Saskia Ilegems
Guy Lambrecht x x x
Pierre Lammens
Claire Liefferinckx x
Triana Lobaton
Edouard Louis x x x x x
Elisabeth Macken x
Marie-Christine Mairlot
Jean-Marc Maisin
Fazia Mana x
Walter Margos
Fady Mokaddem
Kim Moubax
Vinciane Muls
Carmen Musala
Michele Ngassa
Maja Noman
Hanne Ooms
An Outtier
Romy Ouziel
Harald Peeters
Annelies Posen
Philippe Potvin
Lieven Pouillon
Jean-Francois Rahier x x x x x x
Catherine Reenaers x x x
João Sabino
Michael Schapira
Nathalie Schoofs
Nele Schoofs
Alexandra Sermeus
Francoise Smets
Michaël Somers
Dirk Staessen
Marjan Steppe
Beatrijs Strubbe x
Jo Swinnen
Clara Thienpont
Haydeh Vafa
Gert Van Assche
Stephanie Van Biervliet
Frank Van De Mierop
Gaëtan Van Den Steen
Jurgen Van Dongen
Evi Van Dyck
Andre Van Gossum
Philippe Van Hootegem x x
Catherine Van Kemseke
Wouter Van Moerkercke x x x
Steven Van Outryve
Stijn Vanden Branden x x x x
Jo Vandervoort
Gigi Veereman x
Severine Vermeire x x x
Annelies Verreth
Bram Verstockt
Francis Weyn
Barbara Willandt