Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

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Abstract

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

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Figure 1: Power to detect a genetic effect of various sizes (odds ratio 1.2, 1.3 or 1.5) versus study sample size.
Figure 2: A quantile-quantile plot of observed −log10 P values versus the expectation under the null.
Figure 3: Distribution of observed Z scores from the 63 newly identified regions explored, along with the expected distribution under the null (a standard normal with mean 0 and variance 1).
Figure 4: Histogram of percent variance explained by each of the 32 established CD risk loci.

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Acknowledgements

We acknowledge use of DNA from the 1958 British Birth Cohort collection (R. Jones, S. Ring, W. McArdle and M. Pembrey), funded by the Medical Research Council (grant G0000934) and The Wellcome Trust (grant 068545/Z/02), and the UK Blood Services Collection of Common Controls (W. Ouwehand) funded by the Wellcome Trust. We also acknowledge the National Association for Colitis and Crohn's disease and the Wellcome Trust for supporting the case DNA collections, and support from UCB Pharma (unrestricted educational grant) and the NIHR Cambridge Biomedical Research Centre. The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) IBD Genetics Consortium is funded by the following grants: DK62431 (S.R.B.), DK62422 (J.H.C.), DK62420 (R.H.D.), DK62432 and DK064869 (J.D.R.), DK62423 (M.S.S.), DK62413 (K.D.T.), NIH-AI06277 (R.J.X.) and DK62429 (J.H.C.). Additional support was provided by the Burroughs Wellcome Foundation (J.H.C.) and the Crohn's and Colitis Foundation of America (S.R.B., J.H.C.). We thank P. Gregersen and A. Lee (Feinstein Medical Research Institute) for their efforts and the use of control samples. This work was supported by grants from the DGTRE from the Walloon Region (n°315422 and CIBLES), the Communauté Française de Belgique (Biomod ARC), and the Belgian Science Policy organisation (SSTC Genefunc and Biomagnet PAI). E.L., S.Hansoul., D.F. and S.V. are fellows of the Belgian Fonds de la Recherche Scientifique (FNRS) and Fonds Wetenschappelijk Onderzoek-Vlaanderen (NFWO). C.S. is a fellow of the FRIA. We are grateful to all the clinicians, consultants and nursing staff who recruited subjects, including: J.-M. Maisin, V. Muls, J. Van Cauter, M. Van Gossum, P. Closset, P. Hayard and J.M. Ghilain (Erasme-BBIH-IBD); P. Mainguet, F. Mokaddem, F. Fontaine, J. Deflandre and H. Demolin (Ulg collaborators); J.-F. Colombel, M. Lemann, S. Almer, C. Tysk, Y. Finkel, M. Gassul, C. O'Morain, V. Binder and J.-P. Cézard (INSERM collaborators). Sincere thanks to L. Liang for his assistance in accessing the eQTL database, and to F. Merlin for expert technical assistance. Finally, we thank all individuals who contributed samples.

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Correspondence to Mark J Daly.

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This study is a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium

This study is a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium

This study is a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium. A full list of authors is provided in the Supplementary Note

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Supplementary Tables 1–6, Supplementary Note and Supplementary Figures 1 and 2 (PDF 612 kb)

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Barrett, J., Hansoul, S., Nicolae, D. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40, 955–962 (2008) doi:10.1038/ng.175

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