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Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Abstract

Crohn’s disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations1. Genome-wide association studies and subsequent meta-analyses of these two diseases2,3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy4, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

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Figure 1: The IBD genome.
Figure 2: Dissecting the biology of IBD.

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Data deposits

Data have been deposited in the NCBI database of Genotypes and Phenotypes under accession numbers phs000130.v1.p1 and phs000345.v1.p1. Summary statistics for imputed GWAS are available at http://www.broadinstitute.org/mpg/ricopili/. Summary statistics for the meta-analysis markers are available at http://www.ibdgenetics.org/. The 523 causal gene network Cytoscape file is available on request.

References

  1. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012)

    Google Scholar 

  2. Anderson, C. A. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature Genet. 43, 246–252 (2011)

    Article  CAS  Google Scholar 

  3. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nature Genet. 42, 1118–1125 (2010)

    Article  CAS  Google Scholar 

  4. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011)

    Article  CAS  Google Scholar 

  5. Cho, J. H. & Gregersen, P. K. Genomics and the multifactorial nature of human autoimmune disease. N. Engl. J. Med. 365, 1612–1623 (2011)

    Article  CAS  Google Scholar 

  6. Cortes, A. & Brown, M. A. Promise and pitfalls of the Immunochip. Arthritis Res. Ther. 13, 101 (2011)

    Article  Google Scholar 

  7. Zuk, O., Hechter, E., Sunyaev, S. R. & Lander, E. S. The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl Acad. Sci. USA 109, 1193–1198 (2012)

    Article  ADS  CAS  Google Scholar 

  8. Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009)

    Article  Google Scholar 

  9. Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009)

    Article  ADS  CAS  Google Scholar 

  10. Notarangelo, L. D. et al. Primary immunodeficiencies: 2009 update. J. Allergy Clin. Immunol. 124, 1161–1178 (2009)

    Article  CAS  Google Scholar 

  11. Bustamante, J., Picard, C., Boisson-Dupuis, S., Abel, L. & Casanova, J. L. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann. NY Acad. Sci. 1246, 92–101 (2011)

    Article  ADS  CAS  Google Scholar 

  12. Patel, S. Y., Doffinger, R., Barcenas-Morales, G. & Kumararatne, D. S. Genetically determined susceptibility to mycobacterial infection. J. Clin. Pathol. 61, 1006–1012 (2008)

    Article  CAS  Google Scholar 

  13. Zhang, F. et al. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nature Genet. 43, 1247–1251 (2011)

    Article  CAS  Google Scholar 

  14. Holland, S. M. et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007)

    Article  CAS  Google Scholar 

  15. Minegishi, Y. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007)

    Article  ADS  CAS  Google Scholar 

  16. Glocker, E. O. et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009)

    Article  CAS  Google Scholar 

  17. Hu, X. et al. Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496–506 (2011)

    Article  CAS  Google Scholar 

  18. Zhang, B. & Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, Article 17 (2005)

    Article  MathSciNet  Google Scholar 

  19. Greenawalt, D. M. et al. A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res. 21, 1008–1016 (2011)

    Article  CAS  Google Scholar 

  20. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008)

    Article  ADS  CAS  Google Scholar 

  21. Schadt, E. E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008)

    Article  Google Scholar 

  22. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008)

    Article  ADS  CAS  Google Scholar 

  23. Zhong, H. et al. Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet. 6, e1000932 (2010)

    Article  Google Scholar 

  24. Zhu, J. et al. Increasing the power to detect causal associations by combining genotypic and expression data in segregating populations. PLOS Comput. Biol. 3, e69 (2007)

    Article  ADS  MathSciNet  Google Scholar 

  25. Lewis, S. J., Baker, I. & Davey Smith, G. Meta-analysis of vitamin D receptor polymorphisms and pulmonary tuberculosis risk. Int. J. Tuberc. Lung Dis. 9, 1174–1177 (2005)

    CAS  PubMed  Google Scholar 

  26. Li, X. et al. SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta-analysis. PLoS ONE 6, e15831 (2011)

    Article  ADS  CAS  Google Scholar 

  27. Kumar, D. et al. Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 140, 731–743 (2010)

    Article  CAS  Google Scholar 

  28. Glocker, E. O. et al. Infant colitis–it’s in the genes. Lancet 376, 1272 (2010)

    Article  Google Scholar 

  29. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nature Genet. 40, 1319–1323 (2008)

    Article  CAS  Google Scholar 

  30. Bhattacharjee, A., Pal, S., Feldman, G. M. & Cathcart, M. K. Hck is a key regulator of gene expression in alternatively activated human monocytes. J. Biol. Chem. 286, 36709–36723 (2011)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the subjects who contributed samples and the physicians and nursing staff who helped with recruitment globally. UK case collections were supported by the National Association for Colitis and Crohn’s disease; Wellcome Trust grant 098051 (L.J., C.A.A., J.C.B.); Medical Research Council UK; the Catherine McEwan Foundation; an NHS Research Scotland career fellowship (R.K.R.); 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 & 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 British 1958 Birth Cohort DNA collection was funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02, and the UK National Blood Service controls by the Wellcome 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, Digestive and Kidney diseases (NIDDK) IBD Genetics Consortium, which is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.M.), DK076984 (M.J.D.), DK084554 (M.J.D. and D.P.M.) and DK062429 (J.H.C.). Additional funds were provided by funding to J.H.C. (DK062429-S1 and Crohn’s & Colitis Foundation of America, Senior Investigator Award (5-2229)) and R.H.D. (CA141743). K.Y.H. is supported by the National Institutes of Health (NIH) MSTP TG T32GM07205 training award. Cedars-Sinai is supported by USPHS grant PO1DK046763 and the Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds, National Center for Research Resources (NCRR) grant M01-RR00425, UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute (CTSI) Grant (UL1 TR000124-01), the Southern California Diabetes and Endocrinology Research Grant (DERC) (DK063491), The Helmsley Foundation (D.P.M.) and the Crohn's and Colitis Foundation of America (D.P.M.). R.J.X. and A.N.A. are funded by DK83756, AI062773, DK043351 and the Helmsley Foundation. The Netherlands Organization for Scientific Research supported R.K.W. with a clinical fellowship grant (90.700.281) and C.W. (VICI grant 918.66.620). C.W. is also supported by the Celiac Disease Consortium (BSIK03009). 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. S.B. 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 Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, and the Swedish Medical Research Council. D.F. and S.V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. We acknowledge a grant from Viborg Regional Hospital, Denmark. V. Andersen 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 in South Eastern Norway (IBSEN) study group, the Norwegian Bone Marrow Donor Registry (NMBDR), 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 (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation (JDRF) and supported by U01 DK062418. The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.

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R.K.W., R.H.D., D.P.M., C.G.M., J.D.R., E.E.S., M.J.D., A.F., M.P. and S.V. contributed equally to the manuscript. J.H.C., J.C.B., R.K.W., R.H.D., D.P.M., A.F., M.P., C.G.M., J.D.R., S.V., M.D.A. and V. Annese conceived, designed and managed the study and managed the funding. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., R.H.D., D.P.M., M.J.D., M.P. and C.G.M. were involved in manuscript preparation. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., K.Y.H., C.A.A., J.E., K.N., S.L.S., S. Raychaudhuri, Z.W., C.A., A.C., G.B., M.H., X.H., B.Z., C.K.Z., H.Z., J.D.R., E.E.S. and M.J.D. performed or supervised statistical and computational analyses. R.K.W., R.H.D., D.P.M., J.C.L., L.P.S., Y.S., P.G., J.-P.A., T.A., L.A., A.N.A., V. Andersen, J.M.A., L.B., P.A.B., A.B., S.B., C.B., S.C., M.D.A., D.D.J., K.L.D., M.D., C.E., L.R.F., D.F., M.G., C.G., R.G., J.G., A.H., C.H., T.H.K., L.K., S.K., A.L., D.L., E.L., I.C.L., C.W.L., A.R.M., C.M., G.M., J.M., W.N., O.P., C.Y.P., U.P., N.J.P., M.R., J.I.R., R.K.R., J.D.S., M.S., J. Satsangi, S.S., L.A.S., J. Sventoraityte, S.R.T., M.T., H.W.V., M.D.V., C.W., D.C.W., J.W., R.J.X., S.Z., M.S.S., V. Annese, H.H., IIBDGC, S.R.B., J.D.R., G.R.S., C.G.M., A.F., M.P., S.V. and J.H.C. were involved in study subject recruitment and assembling phenotypic data. R.K.W., R.H.D., D.P.M., L.P.S., Y.S., M.M., I.C., E.T., T.B., D.E., K.F., T.H., K.D.T., C.G.M., A.F., M.P. and J.H.C. established DNA collections, genotyping and data management. All authors read and approved the final manuscript before submission.

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Correspondence to Judy H Cho.

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The authors declare no competing financial interests.

Additional information

Lists of participants and their affiliations appear in the Supplementary Information.

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Figures 1-12, full legends for Supplementary Tables 1-6, Supplementary References and a list of IBD Genetics Consortium members – see Supplementary Contents for details. (PDF 6835 kb)

Supplementary Tables

This zipped files contains Supplementary Tables 1-6 as follows: 1 shows the GWAS and Immunochip samples used in the study; 2 contains complete details of 163 IBD loci; 3 contains details of disease overlaps with IMD, PID and MSMD described in section 2 of the methods; 4 contains detailed enrichment statistics for all GO terms and canonical pathways; 5 contains the signals of selection at IBD loci; 6 shows enrichment scores for genes in IBD loci within co-expression modules. Supplementary Table 2, which is contained in this zipped file, has been replaced, as there was an error in the original file. In the ‘Detailed assoc stats’ tab, the ‘IC risk’ and ‘IC_nonrisk’ column labels were inadvertently switched. In addition, clarification of the cohort used to determine the odds ratio (OR) shown in the ‘Detailed assoc stats’ and ‘Main Table’ tabs has been included. This file was replaced online on 31 January 2013. (ZIP 356 kb)

Supplementary Data

This zipped file is a Cytoscape file for the macrophage enriched, omental adipose Bayesian network. (ZIP 722 kb)

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Jostins, L., Ripke, S., Weersma, R. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012). https://doi.org/10.1038/nature11582

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