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

doi:10.1038/nature11582

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

Journal article

Peer reviewed

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

PMCID: PMC3491803

PMID: 23128233

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

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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Title: Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Creators - without role: Luke Jostins - Wellcome Sanger Institute
Stephan Ripke - Harvard University
Rinse K. Weersma - University of Groningen
Richard H. Duerr - University of Pittsburgh
Dermot P. McGovern - F Widjaja Fdn Inflammatory Bowel, Los Angeles, CA 90048 USA
Ken Y. Hui - Yale University
James C. Lee - University of Cambridge
L. Philip Schumm - University of Chicago
Yashoda Sharma - Yale University
Carl A. Anderson - Wellcome Sanger Institute
Jonah Essers - Harvard University
Mitja Mitrovic - University of Groningen
Kaida Ning - Yale University
Isabelle Cleynen - KU Leuven
Emilie Theatre - University of Liège
Sarah L. Spain - Supreme Council Of Health
Soumya Raychaudhuri - Brigham and Women's Hospital
Philippe Goyette - Univ Montreal, Montreal, PQ H1T 1C8, Canada
Zhi Wei - New Jersey Institute of Technology
Clara Abraham - Yale University
Jean-Paul Achkar - Cleveland Clin, Dept Gastroenterol & Hepatol, Inst Digest Dis, Cleveland, OH 44195 USA
Tariq Ahmad - Phillips Exeter Academy
Leila Amininejad - Free Univ Brussels, Erasmus Hosp, Dept Gastroenterol, B-1070 Brussels, Belgium
Ashwin N. Ananthakrishnan - Harvard University
Vibeke Andersen - College Station Medical Center
Jane M. Andrews - Royal Adelaide Hosp, Dept Gastroenterol & Hepatol, Inflammatory Bowel Dis Serv, Adelaide, SA 5000, Australia
Leonard Baidoo - University of Pittsburgh
Tobias Balschun - Univ Kiel, Inst Clin Chem, D-24105 Kiel, Germany
Peter A. Bampton - College Station Medical Center
Alain Bitton - McGill University
Gabrielle Boucher - Univ Montreal, Montreal, PQ H1T 1C8, Canada
Stephan Brand - College Station Medical Center
Carsten Buening - Charité - Universitätsmedizin Berlin
Ariella Cohain - Supreme Council Of Health
Sven Cichon - Life & Brain
Mauro D'Amato - Karolinska Institutet
Dirk De Jong - University of Groningen
Kathy L. Devaney - Harvard University
Marla Dubinsky - College Station Medical Center
Cathryn Edwards - Torbay Hosp, Dept Gastroenterol, Torquay TQ2 7AA, Devon, England
David Ellinghaus - Univ Kiel, Inst Clin Chem, D-24105 Kiel, Germany
Lynnette R. Ferguson - University of Auckland
Denis Franchimont - Free Univ Brussels, Erasmus Hosp, Dept Gastroenterol, B-1070 Brussels, Belgium
Karin Fransen - University of Pittsburgh
Richard Gearry - University of Otago
Michel Georges - University of Liège
Christian Gieger - Helmholtz Zentrum München
Juergen Glas - McGill University
Talin Haritunians - College Station Medical Center
Ailsa Hart - St Marks Hosp, Harrow HA1 3UJ, Middx, England
Chris Hawkey - QueensMed Ctr, Nottingham Digest Dis Ctr, Nottingham NG7 1AW, England
Matija Hedl - Yale University
Xinli Hu - Brigham and Women's Hospital
Tom H. Karlsen - College Station Medical Center
Limas Kupcinskas - College Station Medical Center
Subra Kugathasan - Emory University
Anna Latiano - CASA
Debby Laukens - Ghent University
Ian C. Lawrance - University of Western Australia
Charlie W. Lees - University of Edinburgh
Edouard Louis - University of Liège
Gillian Mahy - Townsville Hosp, Dept Gastroenterol, Townsville, Qld 4810, Australia
John Mansfield - Newcastle University
Angharad R. Morgan - University of Auckland
Craig Mowat - University of Dundee
William Newman - University of Manchester
Orazio Palmieri - CASA
Cyriel Y. Ponsioen - University of Amsterdam
Uros Potocnik - University of Maribor
Natalie J. Prescott - Supreme Council Of Health
Miguel Regueiro - University of Pittsburgh
Jerome I. Rotter - College Station Medical Center
Richard K. Russell - Sick
Jeremy D. Sanderson - Guys & St Thomas NHS Fdn Trust, St Thomas Hosp, Dept Gastroenterol, London SE1 7EH, England
Miquel Sans - Pi
Jack Satsangi - University of Edinburgh
Stefan Schreiber - Univ Kiel, Inst Clin Chem, D-24105 Kiel, Germany
Lisa A. Simms - College Station Medical Center
Jurgita Sventoraityte - College Station Medical Center
Stephan R. Targan - F Widjaja Fdn Inflammatory Bowel, Los Angeles, CA 90048 USA
Kent D. Taylor - F Widjaja Fdn Inflammatory Bowel, Los Angeles, CA 90048 USA
Mark Tremelling - Norwich University
Hein W. Verspaget - Leiden University
Martine De Vos - Ghent University
Cisca Wijmenga - University of Groningen
David C. Wilson - Sick
Juliane Winkelmann - Tech Univ Munich, Inst Human Genet, D-80336 Munich, Germany
Ramnik J. Xavier - Harvard University
Sebastian Zeissig - College Station Medical Center
Bin Zhang - Supreme Council Of Health
Clarence K. Zhang - Yale University
Hongyu Zhao - Yale University
Mark S. Silverberg - University of Toronto
Vito Annese - CASA
Hakon Hakonarson - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Steven R. Brant - Johns Hopkins University
Graham Radford-Smith - College Station Medical Center
Christopher G. Mathew - Supreme Council Of Health
John D. Rioux - Univ Montreal, Montreal, PQ H1T 1C8, Canada
Eric E. Schadt - Supreme Council Of Health
Mark J. Daly - Harvard University
Andre Franke - Univ Kiel, Inst Clin Chem, D-24105 Kiel, Germany
Miles Parkes - University of Cambridge
Severine Vermeire - KU Leuven
Jeffrey C. Barrett - Wellcome Sanger Institute
Judy H. Cho - Yale University
Int IBD Genetics Consortium IIBDGC
Publication Details: Nature (London), Vol.491(7422), pp.119-124
Publisher: Springer Nature
Number of pages: 6
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) M11-1 / Crohn's and Colitis UK NF-SI-0508-10299; NF-SI-0611-10219 / National Institute for Health Research; National Institute for Health & Care Research (NIHR) FR 2821/2-1; BR 1912/6-1 / DFG; German Research Foundation (DFG) BSIK03009 / Celiac Disease Consortium Swedish National Program for IBD Genetics National Institute for Health Research, through the Comprehensive Local Research Network Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine National Health and Medical Research Council, Australia; National Health and Medical Research Council (NHMRC) of Australia 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 Saint Thomas' NationalHealth Service Trust 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 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) CZB/4/540; ETM/137; ETM/75 / Chief Scientist Office G0000934 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); Spanish Government 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) G1002033; G0800675; G0600329; G0800759 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 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 DK063491 / Southern California Diabetes and Endocrinology Research Grant (DERC) Juvenile Diabetes Research Foundation (JDRF); Juvenile Diabetes Research Foundation Karolinska Institutet Ihre Foundation Crohn's and Colitis Foundation of America 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 G0800675; G0800759; G1002033; G0600329 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 098051; 083948/Z/07/Z; 085475/B/08/Z; 085475/Z/08/Z / Wellcome Trust 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 King's College London; General Electric Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds
Identifiers: 9926163408331
Academic Unit: Prince Sattam Bin Abdulaziz University
Language: English
Resource Type: Journal article