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).
Original language | English (US) |
---|---|
Pages (from-to) | 156-167 |
Number of pages | 12 |
Journal | The Lancet |
Volume | 387 |
Issue number | 10014 |
DOIs | |
State | Published - Jan 9 2016 |
ASJC Scopus subject areas
- Medicine(all)
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In: The Lancet, Vol. 387, No. 10014, 09.01.2016, p. 156-167.
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}
TY - JOUR
T1 - Inherited determinants of Crohn's disease and ulcerative colitis phenotypes
T2 - A genetic association study
AU - Cleynen, Isabelle
AU - Boucher, Gabrielle
AU - Jostins, Luke
AU - Schumm, L. Philip
AU - Zeissig, Sebastian
AU - Ahmad, Tariq
AU - Andersen, Vibeke
AU - Andrews, Jane M.
AU - Annese, Vito
AU - Brand, Stephan
AU - Brant, Steven R.
AU - Cho, Judy H.
AU - Daly, Mark J.
AU - Dubinsky, Marla
AU - Duerr, Richard H.
AU - Ferguson, Lynnette R.
AU - Franke, Andre
AU - Gearry, Richard B.
AU - Goyette, Philippe
AU - Hakonarson, Hakon
AU - Halfvarson, Jonas
AU - Hov, Johannes R.
AU - Huang, Hailang
AU - Kennedy, Nicholas A.
AU - Kupcinskas, Limas
AU - Lawrance, Ian C.
AU - Lee, James C.
AU - Satsangi, Jack
AU - Schreiber, Stephan
AU - Théâtre, Emilie
AU - Van Der Meulen-De Jong, Andrea E.
AU - Weersma, Rinse K.
AU - Wilson, David C.
AU - Parkes, Miles
AU - Vermeire, Severine
AU - Rioux, John D.
AU - Mansfield, John
AU - Silverberg, Mark S.
AU - Radford-Smith, Graham
AU - McGovern, Dermot P.B.
AU - Barrett, Jeffrey C.
AU - Lees, Charlie W.
N1 - Funding Information: We thank all the individuals who contributed samples and the physicians and nursing staff who helped with recruitment worldwide. We also thank Prof Gil McVean (professor of Statistical Genetics, Wellcome Trust Centre of Human Genetics, University of Oxford, UK) for thorough review of all statistical methods. UK case collections were supported by the National Association for Colitis and Crohn's disease; Wellcome Trust grants 098051 (JCB) and 098759 (LJ); Medical Research Council UK; the Catherine McEwan Foundation; Peninsula College of Medicine and Dentistry, Exeter; the National Institute for Health Research, through the Comprehensive Local Research Network, and through Biomedical Research Centre awards to Guy's and Saint Thomas' National Health Service Trust, King's College London, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The Wellcome Trust Case Control Consortium projects were supported by Wellcome Trust grants 083948/Z/07/Z, 085475/B/08/Z, and 085475/Z/08/Z. North American collections and data processing were supported by funds to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium, which is funded by the following grants: DK062431 (SRB), DK062422 and DK062429 (LPS, JHC), DK062420 (RHD), DK062432 (JDR), DK062423 (MSS), DK076984 and DK084554 (MJD). Additional funds were provided by funding to JHC (DK062429-S1 and Crohn's & Colitis Foundation of America, Senior Investigator Award [5-2229]), and RHD (CA141743). IBD Research at Cedars-Sinai is supported by grant PO1DK046763 and the Cedars-Sinai F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. DPBM is supported by DK062413, AI067068, and U54DE023789-01, grant HS021747 from the Agency for Healthcare Research and Quality, grant 305479 from the European Union, and the Leona M and Harry B Helmsley Charitable Trust. We also acknowledge the University of Pittsburgh Genomics and Proteomics Core Laboratories who undertook genotyping for the Immunochip project. IC and SV are supported by an FWO grant from the Flemish Funds for Scientific Research (FWO) and received funding from the Interuniversity Attraction Poles programme of the Belgian federal scientific policy office, project P7/43 BeMGI. The University of Liege, Belgium is funded by the Walloon Region (IPSEQ, Crohn & CIBLES projects), by the FEDER, by the Politique Scientifique Fédérale (IAP BeMGI), by the Fonds National de la Recherche Scientifique (FNRS), and by the Communauté Française de Belgique (ARC IBD@ULg). The University of Liege thanks the GIGA-R genotranscriptomic platform for their contribution to genotyping. RKW is supported by a VIDI grant (016.136.308) from the Netherlands Organisation for Scientific Research (NWO). This study was also supported by the German Ministry of Education and Research through the National Genome Research Network, the PopGen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence “Inflammation at Interfaces” and DFG grant no. FR 2821/2-1. SB was supported by DFG BR 1912/6-1 and the Else-Kröner-Fresenius-Stiftung (Else Kröner-Exzellenzstipendium 2010_EKES.32). Italian case collections were supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition and funded by the Italian Ministry of Health GR-2008-1144485. Activities in Sweden were supported by the Swedish Society of Medicine, Ihre Foundation, Örebro University Hospital Research Foundation, Karolinska Institute, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, and the Swedish Research Council (JH 521-2011-2764). We acknowledge a grant from Viborg Regional Hospital, Denmark. VAnd was supported by SHS Aabenraa, Denmark. We acknowledge funding provided by the Royal Brisbane and Women's Hospital Foundation, National Health and Medical Research Council, Australia, and by the European Community (5th PCRDT). We acknowledge the following groups that provided biological samples or data for this study: the Inflammatory Bowel disease in South Eastern Norway (IBSEN) study group, including Bjørn Moum, Morten Vatn, and Marte Lie Hoivik, is acknowledged for providing patients with inflammatory bowel disease and data updates; the Avon Longitudinal Study of Parents and Children; the Human Biological Data Interchange and Diabetes UK; and Banco Nacional de ADN, Salamanca. This research also uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the NIDDK, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation, and supported by U01 DK062418. Funding Information: We thank all the individuals who contributed samples and the physicians and nursing staff who helped with recruitment worldwide. We also thank Prof Gil McVean (professor of Statistical Genetics, Wellcome Trust Centre of Human Genetics, University of Oxford, UK) for thorough review of all statistical methods. UK case collections were supported by the National Association for Colitis and Crohn''s disease; Wellcome Trust grants 098051 (JCB) and 098759 (LJ); Medical Research Council UK; the Catherine McEwan Foundation; Peninsula College of Medicine and Dentistry, Exeter; the National Institute for Health Research, through the Comprehensive Local Research Network, and through Biomedical Research Centre awards to Guy''s and Saint Thomas'' National Health Service Trust, King''s College London, Addenbrooke''s Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The Wellcome Trust Case Control Consortium projects were supported by Wellcome Trust grants 083948/Z/07/Z, 085475/B/08/Z, and 085475/Z/08/Z. North American collections and data processing were supported by funds to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium, which is funded by the following grants: DK062431 (SRB), DK062422 and DK062429 (LPS, JHC), DK062420 (RHD), DK062432 (JDR), DK062423 (MSS), DK076984 and DK084554 (MJD). Additional funds were provided by funding to JHC (DK062429-S1 and Crohn''s & Colitis Foundation of America, Senior Investigator Award [5-2229]), and RHD (CA141743). IBD Research at Cedars-Sinai is supported by grant PO1DK046763 and the Cedars-Sinai F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. DPBM is supported by DK062413, AI067068, and U54DE023789-01, grant HS021747 from the Agency for Healthcare Research and Quality, grant 305479 from the European Union, and the Leona M and Harry B Helmsley Charitable Trust. We also acknowledge the University of Pittsburgh Genomics and Proteomics Core Laboratories who undertook genotyping for the Immunochip project. IC and SV are supported by an FWO grant from the Flemish Funds for Scientific Research (FWO) and received funding from the Interuniversity Attraction Poles programme of the Belgian federal scientific policy office, project P7/43 BeMGI. The University of Liege, Belgium is funded by the Walloon Region (IPSEQ, Crohn & CIBLES projects), by the FEDER, by the Politique Scientifique Fédérale (IAP BeMGI), by the Fonds National de la Recherche Scientifique (FNRS), and by the Communauté Française de Belgique (ARC IBD@ULg). The University of Liege thanks the GIGA-R genotranscriptomic platform for their contribution to genotyping. RKW is supported by a VIDI grant (016.136.308) from the Netherlands Organisation for Scientific Research (NWO). This study was also supported by the German Ministry of Education and Research through the National Genome Research Network, the PopGen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence "Inflammation at Interfaces" and DFG grant no. FR 2821/2-1. SB was supported by DFG BR 1912/6-1 and the Else-Kröner-Fresenius-Stiftung (Else Kröner-Exzellenzstipendium 2010_EKES.32). Italian case collections were supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition and funded by the Italian Ministry of Health GR-2008-1144485. Activities in Sweden were supported by the Swedish Society of Medicine, Ihre Foundation, Örebro University Hospital Research Foundation, Karolinska Institute, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, and the Swedish Research Council (JH 521-2011-2764). We acknowledge a grant from Viborg Regional Hospital, Denmark. VAnd was supported by SHS Aabenraa, Denmark. We acknowledge funding provided by the Royal Brisbane and Women''s Hospital Foundation, National Health and Medical Research Council, Australia, and by the European Community (5th PCRDT). We acknowledge the following groups that provided biological samples or data for this study: the Inflammatory Bowel disease in South Eastern Norway (IBSEN) study group, including BjØrn Moum, Morten Vatn, and Marte Lie Hoivik, is acknowledged for providing patients with inflammatory bowel disease and data updates; the Avon Longitudinal Study of Parents and Children; the Human Biological Data Interchange and Diabetes UK; and Banco Nacional de ADN, Salamanca. This research also uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the NIDDK, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation, and supported by U01 DK062418. Funding Information: We thank all the individuals who contributed samples and the physicians and nursing staff who helped with recruitment worldwide. We also thank Prof Gil McVean (professor of Statistical Genetics, Wellcome Trust Centre of Human Genetics, University of Oxford, UK) for thorough review of all statistical methods. UK case collections were supported by the National Association for Colitis and Crohn''s disease; Wellcome Trust grants 098051 (JCB) and 098759 (LJ); Medical Research Council UK; the Catherine McEwan Foundation; Peninsula College of Medicine and Dentistry, Exeter; the National Institute for Health Research, through the Comprehensive Local Research Network, and through Biomedical Research Centre awards to Guy''s and Saint Thomas'' National Health Service Trust, King''s College London, Addenbrooke''s Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The Wellcome Trust Case Control Consortium projects were supported by Wellcome Trust grants 083948/Z/07/Z, 085475/B/08/Z, and 085475/Z/08/Z. North American collections and data processing were supported by funds to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium, which is funded by the following grants: DK062431 (SRB), DK062422 and DK062429 (LPS, JHC), DK062420 (RHD), DK062432 (JDR), DK062423 (MSS), DK076984 and DK084554 (MJD). Additional funds were provided by funding to JHC (DK062429-S1 and Crohn''s & Colitis Foundation of America, Senior Investigator Award [5-2229]), and RHD (CA141743). IBD Research at Cedars-Sinai is supported by grant PO1DK046763 and the Cedars-Sinai F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. DPBM is supported by DK062413, AI067068, and U54DE023789-01, grant HS021747 from the Agency for Healthcare Research and Quality, grant 305479 from the European Union, and the Leona M and Harry B Helmsley Charitable Trust. We also acknowledge the University of Pittsburgh Genomics and Proteomics Core Laboratories who undertook genotyping for the Immunochip project. IC and SV are supported by an FWO grant from the Flemish Funds for Scientific Research (FWO) and received funding from the Interuniversity Attraction Poles programme of the Belgian federal scientific policy office, project P7/43 BeMGI. The University of Liege, Belgium is funded by the Walloon Region (IPSEQ, Crohn & CIBLES projects), by the FEDER, by the Politique Scientifique F?d?rale (IAP BeMGI), by the Fonds National de la Recherche Scientifique (FNRS), and by the Communaut? Fran?aise de Belgique (ARC IBD@ULg). The University of Liege thanks the GIGA-R genotranscriptomic platform for their contribution to genotyping. RKW is supported by a VIDI grant (016.136.308) from the Netherlands Organisation for Scientific Research (NWO). This study was also supported by the German Ministry of Education and Research through the National Genome Research Network, the PopGen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence "Inflammation at Interfaces" and DFG grant no. FR 2821/2-1. SB was supported by DFG BR 1912/6-1 and the Else-Kr?ner-Fresenius-Stiftung (Else Kr?ner-Exzellenzstipendium 2010_EKES.32). Italian case collections were supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition and funded by the Italian Ministry of Health GR-2008-1144485. Activities in Sweden were supported by the Swedish Society of Medicine, Ihre Foundation, ?rebro University Hospital Research Foundation, Karolinska Institute, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, and the Swedish Research Council (JH 521-2011-2764). We acknowledge a grant from Viborg Regional Hospital, Denmark. VAnd was supported by SHS Aabenraa, Denmark. We acknowledge funding provided by the Royal Brisbane and Women''s Hospital Foundation, National Health and Medical Research Council, Australia, and by the European Community (5th PCRDT). We acknowledge the following groups that provided biological samples or data for this study: the Inflammatory Bowel disease in South Eastern Norway (IBSEN) study group, including Bj?rn Moum, Morten Vatn, and Marte Lie Hoivik, is acknowledged for providing patients with inflammatory bowel disease and data updates; the Avon Longitudinal Study of Parents and Children; the Human Biological Data Interchange and Diabetes UK; and Banco Nacional de ADN, Salamanca. This research also uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the NIDDK, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation, and supported by U01 DK062418. Publisher Copyright: © 2016 Cleynen et al. Open Access article distributed under the terms of CC BY.
PY - 2016/1/9
Y1 - 2016/1/9
N2 - 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).
AB - 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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U2 - 10.1016/S0140-6736(15)00465-1
DO - 10.1016/S0140-6736(15)00465-1
M3 - Article
C2 - 26490195
AN - SCOPUS:84954077730
SN - 0140-6736
VL - 387
SP - 156
EP - 167
JO - The Lancet
JF - The Lancet
IS - 10014
ER -