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

Isabelle Cleynen, Gabrielle Boucher, Luke Jostins, L. Philip Schumm, Sebastian Zeissig, Tariq Ahmad, Vibeke Andersen, Jane M Andrews, Vito Annese, Stephan Brand, Steven R. Brant, Judy H Cho, Mark J Daly, Marla Dubinsky, Richard H. Duerr, Lynnette R. Ferguson, Andre Franke, Richard B. Gearry, Philippe Goyette, Hakon HakonarsonJonas Halfvarson, Johannes R. Hov, Hailang Huang, Nicholas A. Kennedy, Limas Kupcinskas, Ian C. Lawrance, James C. Lee, Jack Satsangi, Stephan Schreiber, Emilie Théâtre, Andrea E. Vander Meulen-De Jong, Rinse K. Weersma, David C. Wilson, International Inflammatory Bowel Disease Genetics Consortium, Miles Parkes, Severine Vermeire, John D. Rioux, John Mansfield, Mark S. Silverberg, Graham Radford-Smith, Dermot P. McGovern, Jeffrey Barrett, Charlie Lees

Research output: Contribution to journalArticleResearchpeer-review

258 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)156-167
Number of pages12
JournalThe Lancet
Volume387
Issue number10014
DOIs
Publication statusPublished - 9 Jan 2016
Externally publishedYes

Cite this

Cleynen, I., Boucher, G., Jostins, L., Philip Schumm, L., Zeissig, S., Ahmad, T., ... Lees, C. (2016). Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: A genetic association study. The Lancet, 387(10014), 156-167. https://doi.org/10.1016/S0140-6736(15)00465-1
Cleynen, Isabelle ; Boucher, Gabrielle ; Jostins, Luke ; Philip Schumm, L. ; Zeissig, Sebastian ; Ahmad, Tariq ; Andersen, Vibeke ; Andrews, Jane M ; Annese, Vito ; Brand, Stephan ; Brant, Steven R. ; Cho, Judy H ; Daly, Mark J ; Dubinsky, Marla ; Duerr, Richard H. ; Ferguson, Lynnette R. ; Franke, Andre ; Gearry, Richard B. ; Goyette, Philippe ; Hakonarson, Hakon ; Halfvarson, Jonas ; Hov, Johannes R. ; Huang, Hailang ; Kennedy, Nicholas A. ; Kupcinskas, Limas ; Lawrance, Ian C. ; Lee, James C. ; Satsangi, Jack ; Schreiber, Stephan ; Théâtre, Emilie ; Vander Meulen-De Jong, Andrea E. ; Weersma, Rinse K. ; Wilson, David C. ; International Inflammatory Bowel Disease Genetics Consortium ; Parkes, Miles ; Vermeire, Severine ; Rioux, John D. ; Mansfield, John ; Silverberg, Mark S. ; Radford-Smith, Graham ; McGovern, Dermot P. ; Barrett, Jeffrey ; Lees, Charlie. / Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : A genetic association study. In: The Lancet. 2016 ; Vol. 387, No. 10014. pp. 156-167.
@article{1418af9aa92640f9af2dea8466b75d93,
title = "Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: A genetic association study",
abstract = "BackgroundCrohn'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.MethodsThis 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.FindingsAfter 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).InterpretationOur 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.",
author = "Isabelle Cleynen and Gabrielle Boucher and Luke Jostins and {Philip Schumm}, L. and Sebastian Zeissig and Tariq Ahmad and Vibeke Andersen and Andrews, {Jane M} and Vito Annese and Stephan Brand and Brant, {Steven R.} and Cho, {Judy H} and Daly, {Mark J} and Marla Dubinsky and Duerr, {Richard H.} and Ferguson, {Lynnette R.} and Andre Franke and Gearry, {Richard B.} and Philippe Goyette and Hakon Hakonarson and Jonas Halfvarson and Hov, {Johannes R.} and Hailang Huang and Kennedy, {Nicholas A.} and Limas Kupcinskas and Lawrance, {Ian C.} and Lee, {James C.} and Jack Satsangi and Stephan Schreiber and Emilie Th{\'e}{\^a}tre and {Vander Meulen-De Jong}, {Andrea E.} and Weersma, {Rinse K.} and Wilson, {David C.} and {International Inflammatory Bowel Disease Genetics Consortium} and Mauro D'Amato and Miles Parkes and Severine Vermeire and Rioux, {John D.} and John Mansfield and Silverberg, {Mark S.} and Graham Radford-Smith and McGovern, {Dermot P.} and Jeffrey Barrett and Charlie Lees",
year = "2016",
month = "1",
day = "9",
doi = "10.1016/S0140-6736(15)00465-1",
language = "English",
volume = "387",
pages = "156--167",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier",
number = "10014",

}

Cleynen, I, Boucher, G, Jostins, L, Philip Schumm, L, Zeissig, S, Ahmad, T, Andersen, V, Andrews, JM, Annese, V, Brand, S, Brant, SR, Cho, JH, Daly, MJ, Dubinsky, M, Duerr, RH, Ferguson, LR, Franke, A, Gearry, RB, Goyette, P, Hakonarson, H, Halfvarson, J, Hov, JR, Huang, H, Kennedy, NA, Kupcinskas, L, Lawrance, IC, Lee, JC, Satsangi, J, Schreiber, S, Théâtre, E, Vander Meulen-De Jong, AE, Weersma, RK, Wilson, DC, International Inflammatory Bowel Disease Genetics Consortium, Parkes, M, Vermeire, S, Rioux, JD, Mansfield, J, Silverberg, MS, Radford-Smith, G, McGovern, DP, Barrett, J & Lees, C 2016, 'Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: A genetic association study', The Lancet, vol. 387, no. 10014, pp. 156-167. https://doi.org/10.1016/S0140-6736(15)00465-1

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : A genetic association study. / Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Philip Schumm, L.; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R.; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H.; Ferguson, Lynnette R.; Franke, Andre; Gearry, Richard B.; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R.; Huang, Hailang; Kennedy, Nicholas A.; Kupcinskas, Limas; Lawrance, Ian C.; Lee, James C.; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; Vander Meulen-De Jong, Andrea E.; Weersma, Rinse K.; Wilson, David C.; International Inflammatory Bowel Disease Genetics Consortium; Parkes, Miles; Vermeire, Severine; Rioux, John D.; Mansfield, John; Silverberg, Mark S.; Radford-Smith, Graham; McGovern, Dermot P.; Barrett, Jeffrey; Lees, Charlie.

In: The Lancet, Vol. 387, No. 10014, 09.01.2016, p. 156-167.

Research output: Contribution to journalArticleResearchpeer-review

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 - Philip Schumm, L.

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 - Vander Meulen-De Jong, Andrea E.

AU - Weersma, Rinse K.

AU - Wilson, David C.

AU - International Inflammatory Bowel Disease Genetics Consortium

AU - D'Amato, Mauro

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.

AU - Barrett, Jeffrey

AU - Lees, Charlie

PY - 2016/1/9

Y1 - 2016/1/9

N2 - BackgroundCrohn'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.MethodsThis 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.FindingsAfter 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).InterpretationOur 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.

AB - BackgroundCrohn'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.MethodsThis 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.FindingsAfter 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).InterpretationOur 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.

UR - http://www.scopus.com/inward/record.url?scp=84954077730&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(15)00465-1

DO - 10.1016/S0140-6736(15)00465-1

M3 - Article

C2 - 26490195

AN - SCOPUS:84954077730

VL - 387

SP - 156

EP - 167

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10014

ER -

Cleynen I, Boucher G, Jostins L, Philip Schumm L, Zeissig S, Ahmad T et al. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: A genetic association study. The Lancet. 2016 Jan 9;387(10014):156-167. https://doi.org/10.1016/S0140-6736(15)00465-1