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

Cleynen, Isabelle, Boucher, Gabrielle, Jostins, Luke, Schumm, L. Philip, Zeissig, Sebastian, Ahmad, Tariq, Andersen, Vibeke, Andrews, Jane M., Annese, Vito, Brand, Stephan, Brant, Steven, Cho, Judy H., Daly, Mark J., Dubinsky, Marla, Duerr, Richard H., Ferguson, Lynnette R., Franke, Andre, Gearry, Richard B., Goyette, Philippe, Hakonarson, Hakon, Halfvarson, Jason, Hov, Johannes R., Huang, Hailang, Kennedy, Nicholas A., Kupcinskas, Limas, Lawrance, Ian C., Lee, James C., Satsangi, Jack, Schreiber, Stephan, Theatre, Emilie, Van Der Meulen-De Jong, Andrea E., Weersma, Rinse K., Wilson, David C., Parkes, Miles, Vermeire, Severine, Rioux, John D., Mansfield, John, Silverberg, Mark S., Radford-Smith, Graham, McGovern, Dermot P. B., Barrett, Jeffrey C. and Lees, Charlie W. (2016) Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. The Lancet, 387 10014: 156-167. doi:10.1016/S0140-6736(15)00465-1


Author Cleynen, Isabelle
Boucher, Gabrielle
Jostins, Luke
Schumm, L. Philip
Zeissig, Sebastian
Ahmad, Tariq
Andersen, Vibeke
Andrews, Jane M.
Annese, Vito
Brand, Stephan
Brant, Steven
Cho, Judy H.
Daly, Mark J.
Dubinsky, Marla
Duerr, Richard H.
Ferguson, Lynnette R.
Franke, Andre
Gearry, Richard B.
Goyette, Philippe
Hakonarson, Hakon
Halfvarson, Jason
Hov, Johannes R.
Huang, Hailang
Kennedy, Nicholas A.
Kupcinskas, Limas
Lawrance, Ian C.
Lee, James C.
Satsangi, Jack
Schreiber, Stephan
Theatre, Emilie
Van Der Meulen-De Jong, Andrea E.
Weersma, Rinse K.
Wilson, David C.
Parkes, Miles
Vermeire, Severine
Rioux, John D.
Mansfield, John
Silverberg, Mark S.
Radford-Smith, Graham
McGovern, Dermot P. B.
Barrett, Jeffrey C.
Lees, Charlie W.
Title Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study
Journal name The Lancet   Check publisher's open access policy
ISSN 1474-547X
0140-6736
Publication date 2016-01-09
Year available 2015
Sub-type Article (original research)
DOI 10.1016/S0140-6736(15)00465-1
Open Access Status DOI
Volume 387
Issue 10014
Start page 156
End page 167
Total pages 12
Place of publication London, United Kingdom
Publisher Lancet Publishing Group
Language eng
Abstract 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.
Formatted 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).
Keyword Crohn’s disease
Ulcerative colitis
Inflammatory bowel disease
Exaggerated mucosal immune response
Genotype association study
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID U54DE023789-01
R01 CA141743
U54 DE023789
083948/Z/07/Z
DK062422
098759
U01 DK062413
DK062429-S1
P30 DK043351
R21 DK084554
DK062423
P30 DK089502
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R01 HS021747
P01DK046763
U01 DK062429
U01 DK062418
U01 DK062422
ETM/75
098051
085475/B/08/Z
DK062431
DK062420
AI067068
R03 DK076984
DK076984
HS021747
U01 DK062423
P30 CA016359
DK062429
U01 AI067068
P01 DK046763
G0800675
DK062432
085475/Z/08/Z
DK062413
U01 DK062420
U01 DK062431
G0600329
DK084554
Institutional Status UQ

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Sub-type: Article (original research)
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