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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.

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Figure 1: Comparison of odds ratios for Crohn's disease and ulcerative colitis risk variants in Europeans and East Asians.
Figure 2: Comparison of variance explained per risk variant for Crohn's disease and ulcerative colitis between East Asians and Europeans.

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Acknowledgements

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).

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Contributions

Study design: J.Z.L., S.v.S., H.H., A.P.M., J.C.B., B.Z.A., M.P., T.B.K., M.J.D., A.F., C.A.A. and R.K.W. Collection of samples and clinical information: S.C.N., J.C.L., S.A., J.H.C., N.E.D., Y.F., A.H., R.C.J., G.J., W.H.K., H.P., W.G.N., V.M., T.R.O., H.V., A.S., J.J.Y.S., R.M., K.Y., S.-K.Y., M.K., T.B.K., A.F. and R.K.W. Quality control and genotype calling: J.Z.L., S.v.S., B.Z.A., H.H., L.J., T.S. and C.A.A. Statistical analyses: J.Z.L., S.v.S., H.H., A.T., L.J., R.A., S.R., H.-J.W., L.F., C.A.A. and R.K.W. Writing of the manuscript: J.Z.L., S.v.S., H.H., J.C.L., J.C., B.Z.A., M.P., C.A.A. and R.K.W.

Corresponding authors

Correspondence to Carl A Anderson or Rinse K Weersma.

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The authors declare no competing financial interests.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and 8–11, Supplementary Tables 4, 8, 10, 11 and 12, and Supplementary Note (PDF 2591 kb)

Supplementary Table 1

Association statistics from the trans-ancestry meta-analysis for all previously identified and novel loci. (XLSX 312 kb)

Supplementary Table 2

Minimal P values for association within each of the 231 IBD loci for each separate ancestral cohort. (XLSX 90 kb)

Supplementary Table 3

Heterogeneity of effect of associations among the four ancestry cohorts. (XLSX 117 kb)

Supplementary Table 5

Association results for the current analysis for all previously reported variants associated with non-European IBD. (XLSX 17 kb)

Supplementary Table 6

Functional Annotation 38 Novel SNPs - Expression Quantitative Trait Loci (eQTL) for the 38 novel IBD risk loci. (XLSX 60 kb)

Supplementary Table 7

ENCODE annotation of the 38 novel IBD risk SNPs. (XLSX 45 kb)

Supplementary Table 9

Functional annotation - GRAIL and DAPPLE results. (XLSX 68 kb)

Supplementary Figure 7

Regional plots for the 38 novel IBD loci. (PDF 7676 kb)

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Liu, J., van Sommeren, S., Huang, H. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 47, 979–986 (2015). https://doi.org/10.1038/ng.3359

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