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Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease


Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; 75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10−15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10−15). Our study represents a substantial advance in understanding of the genetics of PSC.

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Figure 1: Odds ratios (and their 95% confidence intervals) for PSC, UC and CD across the six PSC-associated SNPs demonstrating strong evidence for a shared causal variant (maximum posterior probability > 0.8).
Figure 2: Genome-wide genetic correlation between PSC (and its subphenotypes), CD and UC.


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We thank the patients and healthy controls for their participation, and are grateful to the physicians, scientists and nursing staff who recruited individuals whose data is used in our study. We acknowledge the use of DNA or genotype data from a number of sources, including: the Health and Retirement Study (HSR) conducted by the University of Michigan, funded by the National Institute on Aging (grant numbers U01AG009740, RC2AG036495 and RC4AG039029) and accessed via dbGaP; Popgen 2.0, supported by a grant from the German Ministry for Education and Research (01EY1103); The Mayo Clinic Biobank, supported by the Mayo Clinic Center for Individualized Medicine; the INTERVAL study, undertaken by the University of Cambridge with funding from the National Health Service Blood and Transplant (NHSBT) (the views expressed in this publication are those of the authors and not necessarily those of the NHSBT); the FOCUS biobank. We thank the investigators of the 1000 Genomes and UK10K projects for generating and sharing the population haplotypes and Jie Huang for advice regarding imputation. We thank all members of the International IBD Genetics Consortium for sharing genetic data vital to the success of our study. This study was supported by NoPSC, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK RO1DK084960, KNL), the Wellcome Trust (098759/Z/12/Z: L.J.; 098051: S.-G.J., J.Z.L., T.S., J.G.-A., N.K., D.J.G. and C.A.A.), the Kwanjeong Educational Foundation (S.-G.J.), the German Federal Ministry of Education and Research (B.M.B.F.) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A) and the Chris M. Carlos and Catharine Nicole Jockisch Carlos Endowment in PSC. This project received infrastructure support from the DFG Excellence Cluster 306 “Inflammation at Interfaces” and the PopGen Biobank (Kiel, Germany), an endowment professorship (A.F.) by the Foundation for Experimental Medicine (Zurich, Switzerland). The recruitment of patients in Hamburg was supported by the YAEL-Foundation and the DFG (SFB841). B.A. Lie and the Norwegian Bone Marrow Donor Registry at Oslo University Hospital, Rikshospitalet in Oslo are acknowledged for sharing the healthy Norwegian controls. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (, which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource ( and the NIHR Cambridge Biomedical Research Centre ( The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and NIHR Research Cambridge Biomedical Research Centre. We thank K. Cloppenborg-Schmidt, I. Urbach, I. Pauselis, T. Wesse, T. Henke, R. Vogler, V. Pelkonen, K. Holm, H. Dahlen Sollid, B. Woldseth, J. Andreas and L. Wenche Torbjørnsen for expert help. R.K.W. is supported by a clinical fellowship grant (90.700.281) from the Netherlands Organization for Scientific Research. B.E. receives support from Medical Research Council, United Kingdom. T.M. and D.G. are supported by Deutsche Forschungsgemeinschaft, Grant. A.P. is supported by Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), grant PI071318 Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, and grant PI12/01448, from Ministerio de Economía y Competitvidad, Spain. P.R.D. is supported by Canadian Institutes of Health research (CIHR) and Genome Canada. C.W. is supported by grants from the Celiac Disease Consortium (BSIK03009) and Netherlands Organization for Scientific Research (NWO, VICI grant918.66.620). We acknowledge members of the International PSC Study Group, the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC), and the UK-PSC Consortium for their participation. We thank J. Rud for secretarial support.

Author information

Authors and Affiliations




S.-G.J., B.D.J., N.K., T.S., J.G.-A. and C.A.A. performed statistical data analysis. S.-G.J., B.D.J., S.M., T.F., E.M., E.J.A. and C.A.A. performed initial quality control and sample identification. L.J., J.Z.L., D.J.G., M.d.A. and C.A.A. provided statistical and analytical advice. T.H.K., K.N.L. and C.A.A. coordinated the project and supervised the analyses. S.-G.J., B.D.J., T.H.K., K.N.L. and C.A.A. drafted of the manuscript. E.M.S., K.M.B., A.B., S.V., B.E., P.R.D., M.F., T.M., C.S., M.S., T.J.W., D.N.G., D.E., F.B., A.T., M.L., W.L., G.J., U.B., R.K.W., C.W., H.-U.M., P.M., A.P., K.K., O.C., P.I., E.G., K.S., C.M., J.S., W.H.O., D.J.R., J.D., A.F., A.F.G., J.E.E., S.S., C.C., C.L.B., V.A.L., J.A.O., K.B.C., K.V.K., N.C., M.P.M., B.S., G.M., R.N.S., G.A., R.W.C., G.M.H., S.M.R., A.F., K.N.L., C.A.A., The UK-PSC Consortium, The International IBD Genetics Consortium, and The International PSC Study Group collected the samples, performed clinical ascertainment or coordinated sample logistics. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Konstantinos N Lazaridis or Carl A Anderson.

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Competing interests

The authors declare no competing financial interests.

Additional information

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

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

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Note (PDF 16839 kb)

Supplementary Table 1

Quality control summary for the samples in the discovery (GWAS) cohort. (XLSX 9 kb)

Supplementary Table 2

Summary of post-imputation SNP quality control. (XLSX 8 kb)

Supplementary Table 3

Summary of samples in the replication cohort. (XLSX 9 kb)

Supplementary Table 4

Association summary statistics for the 40 variants that showed suggestive evidence of significance in the discovery cohort and were followed up by replication. (XLSX 17 kb)

Supplementary Table 5

Previously reported genome-wide associations in other immune-mediated diseases. (XLSX 8 kb)

Supplementary Table 6

SIFT and PolyPhen 2 results. (XLSX 9 kb)

Supplementary Table 7

GWAVA results and select gene position annotation. (XLSX 336 kb)

Supplementary Table 8

Prioritized genes for all 18 PSC risk loci. (XLSX 12 kb)

Supplementary Table 9

Colocalization analysis results in the 18 PSC risk loci. (XLSX 16 kb)

Supplementary Table 10

Summary statistics of 18 PSC risk loci in PSC, CD, UC and IBD. (XLSX 14 kb)

Supplementary Table 11

Summary of IBD subphenotypes in the PSC cohort. (XLSX 9 kb)

Supplementary Table 12

Summary of quality control for 40 variants genotyped by Sequenom in the replication analysis. (XLSX 8 kb)

Supplementary Table 13

Summary of quality control for samples included in the genetic correlation analysis. (XLSX 9 kb)

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Ji, SG., Juran, B., Mucha, S. et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet 49, 269–273 (2017).

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