Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Cleynen I1, Boucher G2, Jostins L3, Schumm LP4, Zeissig S5, Ahmad T6, Andersen V7, Andrews JM8, Annese V9, Brand S10, Brant SR11, Cho JH12, Daly MJ13, Dubinsky M14, Duerr RH15, Ferguson LR16, Franke A17, Gearry RB18, Goyette P2, Hakonarson H19, Halfvarson J20, Hov JR21, Huang H13, Kennedy NA22, Kupcinskas L23, Lawrance IC24, Lee JC25, Satsangi J22, Schreiber S26, Théâtre E27, van der Meulen-de Jong AE28, Weersma RK29, Wilson DC30; International Inflammatory Bowel Disease Genetics Consortium, Parkes M25, Vermeire S31, Rioux JD2, Mansfield J32, Silverberg MS33, Radford-Smith G34, McGovern DP35, Barrett JC36, Lees CW37. Lancet. 2015 Oct 18. pii: S0140-6736(15)00465-1. doi: 10.1016/S0140-6736(15)00465-1. [Epub ahead of print]
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1Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium. 2Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada. 3Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Christ Church, University of Oxford, St Aldates, UK. 4Department of Public Health Sciences, University of Chicago, Chicago, IL, USA. 5Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany. 6Peninsula College of Medicine and Dentistry, Exeter, UK. 7Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark. 8Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia. 9Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy; Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy. 10Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany. 11Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. 12Department of Genetics, Yale School of Medicine, New Haven, CT, USA. 13Broad Institute of MIT and Harvard, Cambridge, MA, USA. 14Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA. 15Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. 16School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. 17Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. 18Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand. 19Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 20Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden; School of Health and Medical Sciences, Örebro University, Örebro, Sweden. 21Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway. 22Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. 23Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. 24Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco WA and School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, WA, Australia. 25Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. 26Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany. 27Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium; Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium. 28Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands. 29Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands. 30Child Life and Health, University of Edinburgh, Edinburgh, UK; Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK. 31Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. 32Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK. 33Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada. 34Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, and School of Medicine, University of Queensland, Brisbane, Australia. 35F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 36Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. Electronic address: barrett@sanger.ac.uk. 37Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Electronic address: Charlie.lees@ed.ac.uk.


BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.

METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.

FINDINGS: After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10-78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10-18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10-4).

INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.

FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

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