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

Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium, The International IBD Genetics Consortium (IIBDGC), for The International IBD Genetics Consortium (IIBDGC)

Research output: Contribution to journalArticleResearchpeer-review

2290 Citations (Scopus)

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
Pages (from-to)119-124
Number of pages6
JournalNature
Volume491
Issue number7422
DOIs
Publication statusPublished - 1 Nov 2012

Cite this

Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium, ... for The International IBD Genetics Consortium (IIBDGC) (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119-124. https://doi.org/10.1038/nature11582
Australia and New Zealand IBDGC ; Belgium Genetic Consortium ; Initiative on Crohn and Colitis ; NIDDK IBDGC ; United Kingdom IBDGC ; Wellcome Trust Case Control Consortium ; The International IBD Genetics Consortium (IIBDGC) ; for The International IBD Genetics Consortium (IIBDGC). / 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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Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium, The International IBD Genetics Consortium (IIBDGC) & for The International IBD Genetics Consortium (IIBDGC) 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

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. / Australia and New Zealand IBDGC; Belgium Genetic Consortium; Initiative on Crohn and Colitis; NIDDK IBDGC; United Kingdom IBDGC; Wellcome Trust Case Control Consortium; The International IBD Genetics Consortium (IIBDGC); for The International IBD Genetics Consortium (IIBDGC).

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

Research output: Contribution to journalArticleResearchpeer-review

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 - Philip Schumm, L.

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 - De Jong, Dirk

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 D.

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 - De Vos, Martine

AU - Wijmenga, Cisca

AU - Wilson, David C.

AU - Winkelmann, Juliane

AU - Xavier, Ramnik J.

AU - Zeissig, Sebastian

AU - Zhang, Bin

AU - Zhang, Clarence

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 - Barrett, Jeffrey C.

AU - Vermeire, Severine

AU - Barrett, Jeffrey C.

AU - Cho, Judy H.

AU - Barclay, Murray

AU - Peyrin-Biroulet, Laurent

AU - Chamaillard, Mathias

AU - Colombel, Jean Frederick

AU - Cottone, Mario

AU - Croft, Anthony

AU - D'Incà, Renata

AU - Halfvarson, Jonas

AU - Hanigan, Katherine

AU - Henderson, Paul

AU - Hugot, Jean Pierre

AU - Karban, Amir

AU - Kennedy, Nicholas A.

AU - Azam Khan, Mohammed

AU - Lémann, Marc

AU - Levine, Arie

AU - Massey, Dunecan

AU - Milla, Monica

AU - Montgomery, Grant W.

AU - Evelyn Ng, Sok Meng

AU - Oikonomou, Ioannis

AU - Peeters, Harald

AU - Proctor, Deborah D.

AU - Rahier, Jean Francois

AU - Roberts, Rebecca

AU - Rutgeerts, Paul

AU - Seibold, Frank

AU - Stronati, Laura

AU - Taylor, Kirstin M.

AU - Törkvist, Leif

AU - Ublick, Kullak

AU - Van Limbergen, Johan

AU - Van Gossum, Andre

AU - Vatn, Morten H.

AU - Zhang, Hu

AU - Zhang, Wei

AU - Andrews, Jane M.

AU - Bampton, Peter A.

AU - Barclay, Murray

AU - Florin, Timothy H.

AU - Krishnaprasad, Krupa

AU - Krishnaprasad, Krupa

AU - Lawrance, Ian C.

AU - Mahy, Gillian

AU - Montgomery, Grant W.

AU - Radford-Smith, Graham

AU - Roberts, Rebecca L.

AU - Simms, Lisa A.

AU - Amininijad, Leila

AU - Cleynen, Isabelle

AU - Dewit, Olivier

AU - Franchimont, Denis

AU - Georges, Michel

AU - Laukens, Debby

AU - Peeters, Harald

AU - Rahier, Jean Francois

AU - Rutgeerts, Paul

AU - Theatre, Emilie

AU - Van Gossum, André

AU - Vermeire, Severine

AU - Aumais, Guy

AU - Baidoo, Leonard

AU - Barrie, Arthur M.

AU - Beck, Karen

AU - Bernard, Edmond Jean

AU - Binion, David G.

AU - Bitton, Alain

AU - Brant, Steve R.

AU - Cho, Judy H.

AU - Cohen, Albert

AU - Croitoru, Kenneth

AU - Daly, Mark J.

AU - Datta, Lisa W.

AU - Deslandres, Colette

AU - Duerr, Richard H.

AU - Dutridge, Debra

AU - Ferguson, John

AU - Fultz, Joann

AU - Goyette, Philippe

AU - Greenberg, Gordon R.

AU - Haritunians, Talin

AU - Jobin, Gilles

AU - Katz, Seymour

AU - Lahaie, Raymond G.

AU - McGovern, Dermot P.

AU - Nelson, Linda

AU - Ng, Sok Meng

AU - Ning, Kaida

AU - Oikonomou, Ioannis

AU - Paré, Pierre

AU - Proctor, Deborah D.

AU - Regueiro, Miguel D.

AU - Rioux, John D.

AU - Ruggiero, Elizabeth

AU - Philip Schumm, L.

AU - Schwartz, Marc

AU - Scott, Regan

AU - Sharma, Yashoda

AU - Silverberg, Mark S.

AU - Spears, Denise

AU - Hillary Steinhart, A.

AU - Stempak, Joanne M.

AU - Swoger, Jason M.

AU - Tsagarelis, Constantina

AU - Zhang, Wei

AU - Zhang, Clarence

AU - Zhao, Hongyu

AU - Aerts, Jan

AU - Ahmad, Tariq

AU - Arbury, Hazel

AU - Attwood, Anthony

AU - Auton, Adam

AU - Ball, Stephen G.

AU - Balmforth, Anthony J.

AU - Barnes, Chris

AU - Barrett, Jeffrey C.

AU - Barroso, Inês

AU - Barton, Anne

AU - Bennett, Amanda J.

AU - Bhaskar, Sanjeev

AU - Blaszczyk, Katarzyna

AU - Bowes, John

AU - Brand, Oliver J.

AU - Braund, Peter S.

AU - Bredin, Francesca

AU - Breen, Gerome

AU - Brown, Morris J.

AU - Bruce, Ian N.

AU - Bull, Jaswinder

AU - Burren, Oliver S.

AU - Burton, John

AU - Byrnes, Jake

AU - Caesar, Sian

AU - Cardin, Niall

AU - Clee, Chris M.

AU - Coffey, Alison J.

AU - Connell, John M.C.

AU - Conrad, Donald F.

AU - Cooper, Jason D.

AU - Dominiczak, Anna F.

AU - Downes, Kate

AU - Drummond, Hazel E.

AU - Dudakia, Darshna

AU - Burton, Paul R.

AU - Australia and New Zealand IBDGC

AU - Belgium Genetic Consortium

AU - Initiative on Crohn and Colitis

AU - NIDDK IBDGC

AU - United Kingdom IBDGC

AU - Wellcome Trust Case Control Consortium

AU - The International IBD Genetics Consortium (IIBDGC)

AU - for The International IBD Genetics Consortium (IIBDGC)

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

U2 - 10.1038/nature11582

DO - 10.1038/nature11582

M3 - Article

VL - 491

SP - 119

EP - 124

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7422

ER -

Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium 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