Format

Send to

Choose Destination
Lancet. 2016 Jan 9;387(10014):156-67. doi: 10.1016/S0140-6736(15)00465-1. Epub 2015 Oct 18.

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

Collaborators (170)

Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Anderson CA, Andrews JM, Annese V, Aumais G, Baidoo L, Baldassano RN, Bampton PA, Barclay M, Barrett JC, Bayless TM, Bethge J, Bis JC, Bitton A, Boucher G, Brand S, Brandt B, Brant SR, Büning C, Chew A, Cho JH, Cleynen I, Cohain A, Croft A, Daly MJ, D'Amato M, Danese S, De Jong D, De Vos M, Denapiene G, Denson LA, Devaney K, Dewit O, D'Inca R, Dubinsky M, Duerr RH, Edwards C, Ellinghaus D, Essers J, Ferguson LR, Festen EA, Fleshner P, Florin T, Franchimont D, Franke A, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Goyette P, Green T, Griffiths AM, Guthery SL, Hakonarson H, Halfvarson J, Hanigan K, Haritunians T, Hart A, Hawkey C, Hayward NK, Hedl M, Henderson P, Hu X, Huang H, Hui KY, Imielinski M, Ippoliti A, Jonaitis L, Jostins L, Karlsen TH, Kennedy NA, Khan MA, Kiudelis G, Krishnaprasad K, Kugathasan S, Kupcinskas L, Latiano A, Laukens D, Lawrance IC, Lee JC, Lees CW, Leja M, Van Limbergen J, Lionetti P, Liu JZ, Louis E, Mahy G, Mansfield J, Massey D, Mathew CG, McGovern DP, Milgrom R, Mitrovic M, Montgomery GW, Mowat C, Newman W, Ng A, Ng SC, Ng SM, Nikolaus S, Ning K, Nöthen M, Oikonomou I, Palmieri O, Parkes M, Phillips A, Ponsioen CY, Potocnik U, Prescott NJ, Proctor DD, Radford-Smith G, Rahier JF, Raychaudhuri S, Regueiro M, Rieder F, Rioux JD, Ripke S, Roberts R, Russell RK, Sanderson JD, Sans M, Satsangi J, Schadt EE, Schreiber S, Schumm LP, Scott R, Seielstad M, Sharma Y, Silverberg MS, Simms LA, Skieceviciene J, Spain SL, Steinhart A, Stempak JM, Stronati L, Sventoraityte J, Targan SR, Taylor KM, ter Velde A, Theatre E, Torkvist L, Tremelling M, van der Meulen A, van Sommeren S, Vasiliauskas E, Vermeire S, Verspaget HW, Walters T, Wang K, Wang MH, Weersma RK, Wei Z, Whiteman D, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhang H, Zhang W, Zhao H, Zhao ZZ.

Author information

1
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium.
2
Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
3
Wellcome 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.
4
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
5
Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
6
Peninsula College of Medicine and Dentistry, Exeter, UK.
7
Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark.
8
Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia.
9
Unit 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.
10
Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
11
Meyerhoff 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.
12
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
13
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
14
Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA.
15
Division 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.
16
School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
17
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
18
Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand.
19
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
20
Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden; School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
21
Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
22
Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
23
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
24
Centre 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.
25
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
26
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
27
Unit 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.
28
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands.
29
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands.
30
Child Life and Health, University of Edinburgh, Edinburgh, UK; Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK.
31
Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
32
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
33
Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada.
34
Inflammatory 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.
35
F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
36
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. Electronic address: barrett@sanger.ac.uk.
37
Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Electronic address: Charlie.lees@ed.ac.uk.

Abstract

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).

Comment in

PMID:
26490195
PMCID:
PMC4714968
DOI:
10.1016/S0140-6736(15)00465-1
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center