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 Buening; 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; Juergen 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; Int IBD Genetics Consortium IIBDGC; M Barclay

doi:10.1038/nature11582

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

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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, …

Nature (London), Vol.491(7422), pp.119-124

01/11/2012

DOI: https://doi.org/10.1038/nature11582

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https://hdl.handle.net/10523/34244

Abstract

Multidisciplinary Sciences

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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(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). 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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Record Identifier: 9926517835701891
Title: Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Creators: 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 Buening
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
Juergen 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
Int IBD Genetics Consortium IIBDGC
M Barclay
Publication Details: Nature (London), Vol.491(7422), pp.119-124
Academic Unit: Medicine (UOC)
Publisher: Springer Nature
Grant note: Else Kroner-Fresenius-Stiftung (Else Kroner-Exzellenzstipendium) Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition German Federal Ministry of Education and Research (BMBF); Federal Ministry of Education & Research (BMBF) FR 2821/2-1; BR 1912/6-1 / DFG; German Research Foundation (DFG) G0000934 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) BSIK03009 / Celiac Disease Consortium Swedish National Program for IBD Genetics M11-1 / Crohn's and Colitis UK; Crohn's & Colitis Foundation of America National Institute for Health Research, through the Comprehensive Local Research Network Crohn's and Colitis Foundation of America; Crohn's & Colitis Foundation of America Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine Orebro University Hospital Research Foundation 068545/Z/02 / Wellcome Trust grant; Wellcome Trust NHS Research Scotland career fellowship MSTP TG T32GM07205 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA M01-RR00425 / National Center for Research Resources (NCRR); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) PO1DK046763 / USPHS; United States Department of Health & Human Services; United States Public Health Service Helmholtz Zentrum Munchen-German Research Center for Environmental Health; Helmholtz Association State of Bavaria NF-SI-0611-10219; NF-SI-0508-10299 / National Institute for Health Research; National Institutes of Health Research (NIHR) Saint Thomas' NationalHealth Service Trust National Health and Medical Research Council, Australia; National Health & Medical Research Council (NHMRC) of Australia Swedish Organization for IBD Catherine McEwan Foundation Central Manchester Foundation Trust UK National Blood Service Peninsula College of Medicine and Dentistry, Exeter National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) IBD Genetics Consortium G0800675; G0600329; G1002033; G0800759 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Biomedical ResearchCentre 18475 / Cancer Research UK; Versus Arthritis; Cancer Research UK; Versus Arthritis National Human Genome Research Institute (NHGRI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) UL1 TR000124-01 / UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute (CTSI) National Association for Colitis and Crohn's disease University of Manchester Swedish Society of Medicine 90.700.281; 918.66.620 / Netherlands Organization for Scientific Research; Netherlands Organization for Scientific Research (NWO) European Community (5th PCRDT) National Institute of Child Health and Human Development (NICHD); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Medical Research Council UK; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) German Ministry of Education and Research through the National Genome Research Network G0800675; G0600329; G0800759; G1002033 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) DK063491 / Southern California Diabetes and Endocrinology Research Grant (DERC) Juvenile Diabetes Research Foundation (JDRF); Juvenile Diabetes Research Foundation Karolinska Institutet Ihre Foundation Popgen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ` Inflammation at Interfaces'; German Research Foundation (DFG) Royal Brisbane and Women's Hospital Foundation Helmsley Foundation 098051; 083948/Z/07/Z; 085475/B/08/Z; 085475/Z/08/Z / Wellcome Trust King's College London Swedish Medical Research Council; Swedish Medical Research Council (SMRC) NIDDK, National Institute of Allergy and Infectious Diseases (NIAID) GR-2008-1144485 / Italian Ministry of Health; Ministry of Health, Italy ETM/75; CZB/4/540; ETM/137 / Chief Scientist Office; Chief Scientist Office - Scotland Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds
Date published ; e-published: 01/11/2012
Language: English
Resource Type ; Subtype: Journal article

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

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