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Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

Nature Genetics volume 44, pages 1137–1141 (2012)Cite this article

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Abstract

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10−8), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2 > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non–human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2 > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

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Figure 1: Manhattan plot and list of PBC risk loci that reached genome-wide significance across the Immunochip.
Figure 2: Enrichment of DNase-seq peaks among PBC risk loci in Gm12878 compared to other ENCODE cell lines.

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Acknowledgements

We are grateful to the PBC Foundation for helping us to establish the PBC Genetics Study, for endorsing it and for encouraging members of the Foundation to contribute samples. We thank all of the research nurses who assisted with participant recruitment in collaborating centers. We thank the staff in the UK National Institute for Health Research Clinical Research Network (NIHR CRN) and Clinical Research Collaboration (CRC) Cymru for providing invaluable support. We are grateful to K. Chittock and his colleagues at Source Bioscience for performing DNA extraction. We thank O. Burren for designing the participant database and for providing information technology support. We are grateful to A. Dilthey for providing support regarding HLA*IMP. We thank J. Stone for coordinating Immunochip design and production at Illumina. We also thank the members of each disease consortium who initiated and sustained the cross-disease Immunochip project and shared control genotypes. Finally, we thank the individuals who contributed the DNA samples used in this study.

The PBC sample collection was funded by the Isaac Newton Trust, the PBC Foundation, The Addenborooke's Charitable Trust and the Wellcome Trust (085925/Z/08/Z). The PBC Genetics Study is a portfolio study of the UK NIHR CRN (portfolio reference 5630). The project is also supported by the Wellcome Trust (WT090355/A/09/Z, WT090355/B/09/Z and 098051). Genotyping of samples at the University of Virginia used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the US National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation International and is supported by U01-DK-062418 from the US National Institutes of Health. We would like to thank the UK Medical Research Council and Wellcome Trust for funding the collection of DNA for the British 1958 Birth Cohort (MRC grant G0000934, Wellcome Trust grant 068545/Z/02). We acknowledge use of DNA from The UK Blood Services collection of Common Controls (UKBS collection), funded by Wellcome Trust grant 076113/C/04/Z, by Wellcome Trust/Juvenile Diabetes Research Foundation grant 061858 and by the National Institute of Health Research of England. The collection was established as part of the Wellcome Trust Case Control Consortium. G.F.M. is a Clinical Research Training Fellow of the Medical Research Council (G0800460). G.F.M. is also supported by a Raymond and Beverly Sackler Studentship.

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Author notes

  1. Jimmy Z Liu and Mohamed A Almarri: These authors contributed equally to this work.

  2. Richard N Sandford and Carl A Anderson: These authors jointly directed this work.

Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,

    Jimmy Z Liu, Mohamed A Almarri, Daniel J Gaffney, Luke Jostins, Jeffrey C Barrett & Carl A Anderson

  2. Academic Department of Medical Genetics, Cambridge University, Cambridge, UK

    George F Mells, Darren B Day & Richard N Sandford

  3. Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK

    George F Mells & Graeme J Alexander

  4. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK

    Heather J Cordell

  5. Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK

    Samantha J Ducker, Peter T Donaldson & David E Jones

  6. Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.,

    Michael A Heneghan

  7. The Liver Unit, Queen Elizabeth Hospital, Birmingham, UK

    James M Neuberger

  8. Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK

    Andrew J Bathgate

  9. Hepatology Department, Royal Free Campus, University College London Medical School, London, UK

    Andrew Burroughs

  10. The Liver Unit, St James's University Hospital, Leeds, UK

    Mervyn H Davies

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  1. Jimmy Z Liu
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Consortia

The UK Primary Biliary Cirrhosis (PBC) Consortium

The Wellcome Trust Case Control Consortium 3

Contributions

Study concept and design were performed by D.J.G., G.F.M., L.J., H.J.C., M.A.H., J.M.N., P.T.D., D.E.J., G.J.A., A.J.B., A.B., M.H.D., J.C.B., the WTCCC3 Management Committee (Supplementary Note), R.N.S. and C.A.A. Case ascertainment and phenotyping were performed by S.J.D., D.B.D. and The UK PBC Consortium (Supplementary Note). Control samples were ascertained by The UK Blood Service Controls group (Supplementary Note) and The 1958 Birth Cohort Controls group (Supplementary Note). Genotyping was performed by The WTCCC3 DNA, Genotyping and Informatics group (Supplementary Note). J.Z.L., M.A.A., D.J.G., L.J., The WTCCC3 Data Analysis group (Supplementary Note) and C.A.A. performed statistical analysis. The manuscript was prepared by J.Z.L., M.A.A., D.J.G. and C.A.A. All authors reviewed the final manuscript.

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Correspondence to Carl A Anderson.

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The authors declare no competing financial interests.

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A full list of members and affiliations is provided in the Supplementary Note.

A full list of members and affiliations is provided in the Supplementary Note.

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Supplementary Tables 1–9, Supplementary Figures 1–12 and Supplementary Note (PDF 6160 kb)

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Liu, J., Almarri, M., Gaffney, D. et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet 44, 1137–1141 (2012). https://doi.org/10.1038/ng.2395

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