Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

International Multiple Sclerosis Genetics Consortium; International IBD Genetics Consortium

doi:10.1038/ng.3359

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

International Multiple Sclerosis Genetics Consortium, International IBD Genetics Consortium

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

809 Citations (Scopus)

Abstract

Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

Original language	English
Pages (from-to)	979-986
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	9
DOIs	https://doi.org/10.1038/ng.3359
Publication status	Published - 2015 Aug 27

Bibliographical note

Funding Information:
R.K.W. is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO) and the Broad Medical Research Program of the Broad Foundation (IBD-0318). L.F. is supported by the Netherlands Organization for Scientific Research (NWO), through NWO VENI grant 916.10.135 and NWO VIDI grant 917.14.374. The research leading to these results has received funding from the European Community’s Health Seventh Framework Programme (FP7/2007–2013) under grant agreement 259867. T.B.K. is supported by Centre of Excellence grant BT/01/COE/07/UDSC/2008 from the Department of Biotechnology of the government of India (New Delhi, India). The collection of Iranian samples has been supported by the Tehran University of Medical Sciences, Iran. UK case collections were supported by the National Association for Colitis and Crohn’s Disease, the Wellcome Trust, the Medical Research Council UK and the Peninsular College of Medicine and Dentistry, Exeter. We also acknowledge National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Trust/King’s College London and to Addenbrooke’s Hospital/University of Cambridge School of Clinical Medicine. A.P.M. is supported by the Wellcome Trust under award WT098017. J.Z.L., T.S., J.C.B. and C.A.A. are supported by the Wellcome Trust (098051).

All Science Journal Classification (ASJC) codes

Genetics

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@article{d38c7efe61fc4bf9bcc71d7acad0c7da,

title = "Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations",

abstract = "Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.",

author = "{International Multiple Sclerosis Genetics Consortium} and {International IBD Genetics Consortium} and Liu, {Jimmy Z.} and {Van Sommeren}, Suzanne and Hailiang Huang and Ng, {Siew C.} and Rudi Alberts and Atsushi Takahashi and Stephan Ripke and Lee, {James C.} and Luke Jostins and Tejas Shah and Shifteh Abedian and Cheon, {Jae Hee} and Judy Cho and Daryani, {Naser E.} and Lude Franke and Yuta Fuyuno and Ailsa Hart and Juyal, {Ramesh C.} and Garima Juyal and Kim, {Won Ho} and Morris, {Andrew P.} and Hossein Poustchi and Newman, {William G.} and Vandana Midha and Orchard, {Timothy R.} and Homayon Vahedi and Ajit Sood and Sung, {Joseph J.Y.} and Reza Malekzadeh and Westra, {Harm Jan} and Keiko Yamazaki and Yang, {Suk Kyun} and Barrett, {Jeffrey C.} and Andre Franke and Alizadeh, {Behrooz Z.} and Miles Parkes and Thelma, {B. K.} and Daly, {Mark J.} and Michiaki Kubo and Anderson, {Carl A.} and Weersma, {Rinse K.}",

note = "Funding Information: R.K.W. is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO) and the Broad Medical Research Program of the Broad Foundation (IBD-0318). L.F. is supported by the Netherlands Organization for Scientific Research (NWO), through NWO VENI grant 916.10.135 and NWO VIDI grant 917.14.374. The research leading to these results has received funding from the European Community{\textquoteright}s Health Seventh Framework Programme (FP7/2007–2013) under grant agreement 259867. T.B.K. is supported by Centre of Excellence grant BT/01/COE/07/UDSC/2008 from the Department of Biotechnology of the government of India (New Delhi, India). The collection of Iranian samples has been supported by the Tehran University of Medical Sciences, Iran. UK case collections were supported by the National Association for Colitis and Crohn{\textquoteright}s Disease, the Wellcome Trust, the Medical Research Council UK and the Peninsular College of Medicine and Dentistry, Exeter. We also acknowledge National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Trust/King{\textquoteright}s College London and to Addenbrooke{\textquoteright}s Hospital/University of Cambridge School of Clinical Medicine. A.P.M. is supported by the Wellcome Trust under award WT098017. J.Z.L., T.S., J.C.B. and C.A.A. are supported by the Wellcome Trust (098051).",

year = "2015",

month = aug,

day = "27",

doi = "10.1038/ng.3359",

language = "English",

volume = "47",

pages = "979--986",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

AU - International Multiple Sclerosis Genetics Consortium

AU - International IBD Genetics Consortium

AU - Liu, Jimmy Z.

AU - Van Sommeren, Suzanne

AU - Huang, Hailiang

AU - Ng, Siew C.

AU - Alberts, Rudi

AU - Takahashi, Atsushi

AU - Ripke, Stephan

AU - Lee, James C.

AU - Jostins, Luke

AU - Shah, Tejas

AU - Abedian, Shifteh

AU - Cheon, Jae Hee

AU - Cho, Judy

AU - Daryani, Naser E.

AU - Franke, Lude

AU - Fuyuno, Yuta

AU - Hart, Ailsa

AU - Juyal, Ramesh C.

AU - Juyal, Garima

AU - Kim, Won Ho

AU - Morris, Andrew P.

AU - Poustchi, Hossein

AU - Newman, William G.

AU - Midha, Vandana

AU - Orchard, Timothy R.

AU - Vahedi, Homayon

AU - Sood, Ajit

AU - Sung, Joseph J.Y.

AU - Malekzadeh, Reza

AU - Westra, Harm Jan

AU - Yamazaki, Keiko

AU - Yang, Suk Kyun

AU - Barrett, Jeffrey C.

AU - Franke, Andre

AU - Alizadeh, Behrooz Z.

AU - Parkes, Miles

AU - Thelma, B. K.

AU - Daly, Mark J.

AU - Kubo, Michiaki

AU - Anderson, Carl A.

AU - Weersma, Rinse K.

N1 - Funding Information: R.K.W. is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO) and the Broad Medical Research Program of the Broad Foundation (IBD-0318). L.F. is supported by the Netherlands Organization for Scientific Research (NWO), through NWO VENI grant 916.10.135 and NWO VIDI grant 917.14.374. The research leading to these results has received funding from the European Community’s Health Seventh Framework Programme (FP7/2007–2013) under grant agreement 259867. T.B.K. is supported by Centre of Excellence grant BT/01/COE/07/UDSC/2008 from the Department of Biotechnology of the government of India (New Delhi, India). The collection of Iranian samples has been supported by the Tehran University of Medical Sciences, Iran. UK case collections were supported by the National Association for Colitis and Crohn’s Disease, the Wellcome Trust, the Medical Research Council UK and the Peninsular College of Medicine and Dentistry, Exeter. We also acknowledge National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Trust/King’s College London and to Addenbrooke’s Hospital/University of Cambridge School of Clinical Medicine. A.P.M. is supported by the Wellcome Trust under award WT098017. J.Z.L., T.S., J.C.B. and C.A.A. are supported by the Wellcome Trust (098051).

PY - 2015/8/27

Y1 - 2015/8/27

N2 - Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

AB - Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

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U2 - 10.1038/ng.3359

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