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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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.
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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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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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Luke Jostins
Since this paper was published other scientists have pointed out that the interpretation of the selections signals on IBD loci may be more complex than the story that we present here. For instance, further analysis of the selection data suggests that the "balancing selection" signal could also be explained by recent local selection in Europeans.
Read more here about this on the Genomes Unzipped blog: Looking closer at natural selection in inflammatory bowel disease
Ramon Juste
I have read with great interest this paper and I would like to add some evidence supporting the mycobacterial links pointed out in it, as well as comment on some the consequence of lack of a broader, more comparative, perspective on the etiology of these diseases.
A relationship of human intestinal inflammatory disease with the mycobacterial counterpart in ruminants was already pointed out in 1913^6^, even before the index des cription of Crohn?s disease^5^, on the grounds of the pathological similarities between human regional intestinal inflammatory disease and ruminant paratuberculosis. This mycobacterial hypothesis, thus, linked the human form to the ruminant entity first reported in 1895^9^ and generally accepted to be caused by Mycobacterium avium subsp. paratuberculosis (MAP). This microorganism is a bacterial species characterized as slow and fastidious to grow even in specific isolation media. Since its first isolation from human patients by Chiodini et al in 1984^2^, this agent has been repeatedly linked to CD by immunologic^7,14^, epidemoiologic^1,10^, therapeutic^8^ and genetic^4^ approaches. The paper by Jostins et al. more strongly confirms that and brings out a rare disease (mendelian susceptibility to mycobacteria disease-MSMD) that was already postulated as a model for Crohn?s disease 4 years ago on the grounds of the significantly higher levels of circulating IFN-g in the blood of patients than in the blood of controls^13^. In that disease, a deficiency in the IFN-g receptors would disrupt normal transition from innate to adaptive immune response and cause higher levels of IFN-g in blood because of failure to metabolize it through its receptors.
The mycobacterial etiology hypothesis for human inflammatory disease has faced generalized criticism and disinterest among the gastroenterology community and, in our closer Spanish medical community, has prevented testing the apparent effects of certain treatment patterns that in preliminary ?post hoc? analysis seemed to decrease both the blood MAP DNA levels and the disease activity indices^12^. Unfortunately this is coupled with reluctance of the veterinary authorities of most countries to allow the use of the most efficient control measure against paratuberculosis which is vaccination^11,3^. This is a radical approach grounded on a fundamentalist interpretation of interference with bovine tuberculosis tests results (even though bovine TB has become a highly compartmentalized, if increasingly concerning, animal infection and a nearly negligible zoonosis in the countries that have successfully run those schedules). This has caused a silencing of ongoing vaccination practice in cattle, and nearly so in other species except for the successfull recent introduction of vaccination for control of sheep paratuberculosis in Australia.
All this has left the study of relationships of paratuberculosis and Crohn?s disease nearly orphan but for the efforts of a few researchers that cannot collect enough resources to conduct the right research and that generally also miss the deepening of the study of natural disease as a model of intestinal inflammatory disease. On the contrary vast amounts of public funding are devoted to the study of palliative treatments in humans and on paratuberculosis control programs that have repeatedly proven to fail to cure or to eradicate the infection, but that keep patients and farmers chained to long-term expensive programs. The combined result is that cattle production is less efficient and that human population remains exposed and unprotected in front of high environmental levels of the potential cause of such a common and devastating disease. I hope that the current paper will boost research in the trans-species inflammatory hypothesis and thus bring prompt relief to so many intestinal inflammatory patients currently sentenced to a life of symptomatic therapy.
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