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


RESULTS
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)).


CONCLUSIONS
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.


BACKGROUND
International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium.
Isabelle
I
Cleynen
Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
Gabrielle
G
Boucher
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.
Luke
L
Jostins
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
L Philip
LP
Schumm
Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
Sebastian
S
Zeissig
Peninsula College of Medicine and Dentistry, Exeter, UK.
Tariq
T
Ahmad
Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark.
Vibeke
V
Andersen
Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia.
Jane M
JM
Andrews
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.
Vito
V
Annese
Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Stephan
S
Brand
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.
Steven R
SR
Brant
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Judy H
JH
Cho
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mark J
MJ
Daly
Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA.
Marla
M
Dubinsky
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.
Richard H
RH
Duerr
School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Lynnette R
LR
Ferguson
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
Andre
A
Franke
Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand.
Richard B
RB
Gearry
Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
Philippe
P
Goyette
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Hakon
H
Hakonarson
Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden; School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
Jonas
J
Halfvarson
Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
Johannes R
JR
Hov
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Hailang
H
Huang
Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Nicholas A
NA
Kennedy
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Limas
L
Kupcinskas
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.
Ian C
IC
Lawrance
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
James C
JC
Lee
Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Jack
J
Satsangi
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
Stephan
S
Schreiber
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.
Emilie
E
Théâtre
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands.
Andrea E
AE
van der Meulen-de Jong
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands.
Rinse K
RK
Weersma
Child Life and Health, University of Edinburgh, Edinburgh, UK; Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK.
David C
DC
Wilson
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
Miles
M
Parkes
Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
Severine
S
Vermeire
Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
John D
JD
Rioux
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
John
J
Mansfield
Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada.
Mark S
MS
Silverberg
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.
Graham
G
Radford-Smith
F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Dermot P B
DP
McGovern
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. Electronic address: barrett@sanger.ac.uk.
Jeffrey C
JC
Barrett
Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Electronic address: Charlie.lees@ed.ac.uk.
Charlie W
CW
Lees
D000328:Adult; D000483:Alleles; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D007118:Immunoassay; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D018570:Risk Assessment; D055815:Young Adult
D059811:HLA-DRB1 Chains; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor