Abstract
Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation1,2,3. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip4. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
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Acknowledgements
We thank all individuals with PSC and healthy controls for their participation, and we are indebted to all physicians and nursing staff who recruited subjects. We thank T. Wesse, T. Henke, S. Sedghpour Sabet, R. Vogler, G. Jacobs, I. Urbach, W. Albrecht, V. Pelkonen, V. Barbu, K. Holm, H. Dahlen Sollid, B. Woldseth, J.A. Anmarkrud and L.W. Torbjørnsen for expert help. U. Beuers, F. Braun, W. Kreisel, T. Berg and R. Günther are acknowledged for contributing German individuals with PSC. B.A. Lie and The Norwegian Bone Marrow Donor Registry at Oslo University Hospital, Rikshospitalet (Oslo, Norway) and the Nord-Trøndelag Health Study (HUNT) are acknowledged for sharing healthy Norwegian controls. Banco Nacional de ADN (Salamanca, Spain) is acknowledged for providing Spanish control samples. This study makes use of genotyping data generated by the Dietary, Life style and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) consortium (see URLs), the Cooperative Research in the Region of Augsburg (KORA) study and the Heinz Nixdorf Recall (Risk Factors, Evaluation of Coronary Calcification, and Lifestyle) study. We acknowledge the members of the International PSC Study Group, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Inflammatory Bowel Disease Genetics Consortium (IBDGC), the UK-PSC Consortium and the Alberta IBD Consortium for their participation. J. Barrett is acknowledged for contributions to the design of the Immunochip experiment. Individuals who have shared summary statistics and statistical software are acknowledged in the Supplementary Note.
The study was supported by The Norwegian PSC Research Center (see URLs), by the German Ministry of Education and Research through the National Genome Research Network (01GS0809-GP7), by the Deutsche Forschungsgemeinschaft (FR 2821/2-1), by the EU Seventh Framework Programme FP7/2007-2013 (262055) ESGI, by the Integrated Research and Treatment Center–Transplantation (01EO0802) and by the PopGen Biobank (see URLs). J.Z.L., T.S. and C.A.A. are supported by a grant from the Wellcome Trust (098051). Additional financial support of the study and the coauthors is listed in the Supplementary Note.
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J.Z.L., J.R.H., T.F., E.E., N.T.D., I.T., G.M., I.R.K., O.A.A., W.K.T., A.M.D., T.S. and C.A.A. performed data and statistical analyses. A. Franke, C.A.A. and T.H.K. coordinated the project and supervised the data analysis. J.Z.L., J.R.H., T.F., E.E., A. Franke, C.A.A. and T.H.K. drafted the manuscript. S.M.R., R.K.W., T.J.W., B.E., P.I., G.M.H., D.N.G., A.P., D.E., B.D.J., P.M., C.R., C.S., T.M., B.S., G.D., M.M.N., S.H., J.W., M.M., F.B., C.Y.P., P.J.P.C., M. Sterneck, A.T., A.L.M., J.S., V.L., R.D., D.A., A. Floreani, S.O.-G., S.S.R., A.J.S., S.N., K.H., I.C., J.G.-A., I.R.-P., D.v.H., E.B., R.N.S., P.R.D., E.M., M.H.V., M.S.S., R.H.D., L.P., S.B., M. Sans, V.A., J.-P.A., K.M.B., H.-U.M., O.C., C.L.B., C.W., E.S., S.V., M.A., J.D.R., G.A., A.B., J.C., S.S., M.P.M., M.F., R.W.C., K.N.L., The UK-PSC Consortium, The International IBD Consortium and The International PSC Study Group contributed to the ascertainment of affected individuals and/or sample and clinical data collection. All authors revised the manuscript for critical content and approved the final version.
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Further details appear in the Supplementary Note.
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Further details appear in the Supplementary Note.
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Supplementary Text and Figures
Supplementary Figures 1–16, Supplementary Tables 1–7, 10, 11, 16 and 17, Supplementary Note (PDF 8843 kb)
Supplementary Table 8
Association analysis for the classical HLA class I genes (Separate Excel file). (XLSX 94 kb)
Supplementary Table 9
Association analysis for the classical HLA class II genes. (Separate Excel file). (XLSX 91 kb)
Supplementary Table 12
Genes closest to the PSC and IBD lead SNPs considered for inclusion in the PSC&IBD functional similarity network shown in Supplemetary Figure 9 (Separate Excel file). (XLSX 56 kb)
Supplementary Table 13
Lead SNPs in 33 pleiotropic loci with false discovery rate(FDR)<0.001 given associations in at least one of seven diseases associated with PSC (Separate Excel file). (XLSX 179 kb)
Supplementary Table 14
Lead SNPs in 89 pleiotropic loci with 0.01<false discovery rate(FDR)<0.001 given associations in at least one of seven diseases associated with PSC (Separate Excel file). (XLSX 60 kb)
Supplementary Table 15
Genes within 0.1 cM of all PSC SNPs considered for inclusion in the PSC functional similarity network shown in Supplementary Figure 13(Separate Excel file). (XLSX 55 kb)
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Liu, J., Hov, J., Folseraas, T. et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 45, 670–675 (2013). https://doi.org/10.1038/ng.2616
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DOI: https://doi.org/10.1038/ng.2616
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