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Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Nature Genetics volume 43, pages 329–332 (2011)Cite this article

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A Corrigendum to this article was published on 27 October 2011

This article has been updated

Abstract

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10−8) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

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Change history

  • 12 October 2011

    In the version of this article initially published, three authors, Paul Richardson, Ikram Nasr and Richard Aspinall, were inadvertently omitted from the list of the members of the UK PBC Consortium provided in the Supplementary Note. The error has been corrected in the supplementary information file.

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Acknowledgements

The PBC sample collection was funded by the Isaac Newton Trust, the PBC Foundation and the Wellcome Trust (085925/Z/08/Z). The PBC Genetics Study is a portfolio study of the National Institute for Health Research Comprehensive Clinical Research Network (NIHR CRN, portfolio reference 5630). The WTCCC3 project is also supported by the Wellcome Trust (WT090355/A/09/Z, WT090355/B/09/Z). 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. C.J.H. is an NIHR Senior Research Fellow. C.A.A. is funded by the Wellcome Trust (WT91745/Z/10/Z).

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 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 their efforts. We thank O. Burren for designing the participant database and for providing information technology support. We acknowledge the Department of Twin Research and Genetic Epidemiology, King's College London for additional control genotype data, which was part-funded by a US National Institutes of Health National Eye Institute grant 1RO1EY018246 (PI, T. Young) and genotyping by the NIH Center for Inherited Disease Research (CIDR), with additional genotyping performed at the Wellcome Trust Sanger Institute. The study also received support from the NIHR comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust partnering King's College London. Finally, we thank the individuals who contributed samples used in this study.

Author information

Author notes

  1. George F Mells, James A B Floyd and Katherine I Morley: 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. Academic Department of Medical Genetics, Cambridge University, Cambridge, UK

    George F Mells, Darren B Day, Agnes W Muriithi, Elizabeth F Wheater & Richard N Sandford

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

    George F Mells, Muhammad F Dawwas & Graeme J Alexander

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

    James A B Floyd, Katherine I Morley, Christopher S Franklin, So-Youn Shin, Leena Peltonen & Carl A Anderson

  4. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Australia

    Katherine I Morley

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

    Heather J Cordell

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

    Peter T Donaldson, Samantha J Ducker & David E Jones

  9. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK

    Christopher J Hammond

Authors
  1. George F Mells
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  2. James A B Floyd
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  18. Graeme J Alexander
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Consortia

The UK PBC Consortium

The Wellcome Trust Case Control Consortium 3

Contributions

Study concept and design: G.F.M., H.J.C., M.A.H., J.M.N., P.T.D., the WTCCC3 management committee (see Supplementary Note), L.P., D.E.J., G.J.A., R.N.S., C.A.A.

PBC Genetics Study management: G.F.M., D.B.D., S.J.D., A.W.M., E.F.W., R.N.S.

Case ascertainment and phenotyping: G.F.M., D.B.D., S.J.D., A.W.M., E.F.W., M.F.D., The UK PBC Consortium (see Supplementary Note), D.E.J., G.J.A., R.N.S.

Control sample ascertainment: The UK Blood Service Controls group (see Supplementary Note), The 1958 Birth Cohort Controls group (see Supplementary Note), C.J.H., C.A.A.

Genotyping: The WTCCC3 DNA, Genotyping and Informatics group (see Supplementary Note).

Statistical analysis: J.A.B.F., K.I.M., H.J.C., C.S.F., S.-Y.S., The WTCCC3 data analysis group (see Supplementary Note), C.A.A.

Manuscript preparation: G.F.M., J.A.B.F., K.I.M., H.J.C., D.E.J., G.J.A., R.N.S., C.A.A.

Corresponding authors

Correspondence to Richard N Sandford or Carl A Anderson.

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Competing interests

The authors declare no competing financial interests.

Additional information

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

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

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–10, Supplementary Figures 1–7 and Supplementary Note. (PDF 2421 kb)

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Mells, G., Floyd, J., Morley, K. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 43, 329–332 (2011). https://doi.org/10.1038/ng.789

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