International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Nature Communications, Sep 2015

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine–cytokine pathways, for which relevant therapies exist.

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International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways Heather J. Cordell 8 Younghun Han 9 George F. Mells 10 Yafang Li 9 Gideon M. Hirschfield 11 Casey S. Greene 12 Gang Xie 13 Brian D. Juran 14 Dakai Zhu 9 David C. Qian 9 James A.B. Floyd 15 16 Katherine I. Morley 15 17 Daniele Prati 0 Ana Lleo 1 Daniele Cusi 2 3 Canadian-US PBC Consortium Italian PBC Genetics Study Group UK-PBC Consortium M. Eric Gershwin 4 Carl A. Anderson 15 Konstantinos N. Lazaridis 14 Pietro Invernizzi 1 4 Michael F. Seldin 4 Richard N. Sandford 10 Christopher I. Amos 9 Katherine A. Siminovitch 5 6 7 13 0 Department of Transfusion Medicine and Hematology, Ospedale Alessandro Manzoni , Lecco 23900 , Italy 1 Center for Autoimmune Liver Diseases, IRCCS Instituto Clinico Humanitas , 20089 Rozzano , Italy 2 Universita` degli Studi di Milano , Milan 20129 , Italy 3 Istituto di Tecnologie Biomediche Consiglio Nazionale delle Ricerche , Via Fratelli Cervi, 93, 20090 Segrate, Milan , Italy 4 University of California - Davis , Davis, California 95616 , USA 5 Department of Medicine, University of Toronto , Toronto, Ontario , Canada M5G 1X5 6 Department of Immunology, University of Toronto , Toronto, Ontario , Canada M5G 1X5 7 Department of Molecular Genetics, University of Toronto 8 Institute of Genetic Medicine, Newcastle University , Newcastle upon Tyne NE1 3BZ , UK 9 Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College , Lebanon, New Hampshire 03755 , USA 10 Academic Department of Medical Genetics, Cambridge University , Cambridge CB2 0QQ , UK 11 Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham , Birmingham B15 2TT , UK 12 Department of Genetics, Institute for Quantitative Biomedical Sciences, Geisel School of Medicine, Dartmouth College , Hanover, New Hampshire 03755 , USA 13 Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute , Toronto, Ontario M5G 1X5 , Canada 14 Center for Basic Research in Digestive Diseases, Mayo Clinic , Rochester, Minnesota 55905 , USA 15 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus , Hinxton CB10 1SA , UK 16 William Harvey Research Institute, Queen Mary University of London , London EC1M 6BQ , UK 17 Institute of Psychiatry, Psychology & Neuroscience, Kings College London , London SE5 8AF , UK 18 Abertawe Bro Morgannwg University Health Board, Morriston Hospital , Heol Maes Eglwys, Morriston, Swansea SA6 6NL , UK 19 Betsi Cadwaladr University Health Board, Llandudno General Hospital , Hospital Road, Llandudno LL30 1LB , UK 20 Abertawe Bro Morgannwg University Health Board, Singleton Hospital , Sketty Lane, Sketty, Swansea SA2 8QA , UK 21 Betsi Cadwaladr University Health Board, Wrexham Maelor Hospital , Croesnewydd Road, Wrexham LL13 7TD , UK 22 Abertawe Bro Morgannwg University Health Board, Neath Port Talbot Hospital , Baglan Way, Port Talbot SA12 7BX , UK 23 Abertawe Bro Morgannwg University Health Board, Princess of Wales Hospital , Coity Road, Bridgend CF31 1RQ , UK 24 Blackpool Teaching Hospitals NHS Foundation Trusts, Blackpool Victoria Hospital , Whinney Heys Road, Blackpool FY3 8NR , UK 25 Bolton NHS Foundation Trust, Royal Bolton Hospital , Minerva Road, Farnworth, Bolton BL4 0JR , UK 26 Aintree University Hospitals NHS Foundation Trust, Aintree University Hospital , Longmoor Lane, Liverpool L9 7AL , UK 27 Bradford Teaching Hospitals NHS Foundation Trust, Bradford Royal Infirmary , Duckworth Lane, Bradford BD9 6RJ , UK 28 Airedale NHS Foundation Trust, Airedale General Hospital , Skipton Road, Steeton, Keighley BD20 6TD , UK 29 Brighton and Sussex University Hospitals NHS Trust, Princess Royal Hospital , Lewes Road, Haywards Heath RH16 4EX , UK 30 Aneurin Bevan University Health Board, Nevill Hall Hospital , Brecon Road, Abergavenny NP7 7EG , UK 31 Brighton and Sussex University Hospitals NHS Trust, Royal Sussex County Hospital , Eastern Road, Brighton BN2 5BE , UK 32 Aneurin Bevan University Health Board, Royal Gwent Hospital , Cardiff Road, Newport NP20 2UB , UK 33 Buckinghamshire Healthcare NHS Trust, Amersham Hospital , Whielden Street, Amersham HP7 0JD , UK 34 Aneurin Bevan University Health Board, Ysbyty Ystrad Fawr , Ystrad Fawr Way, Ystrad Mynach, Hengoed CF82 7EP , UK 35 Buckinghamshire Healthcare NHS Trust, Stoke Mandeville Hospital , Mandeville Road, Aylesbury HP21 8AL , UK 36 Ashford & St Peter's Hospitals NHS Foundation Trust, Ashford Hospital , London Road, Ashford TW15 3AA , UK 37 Buckinghamshire Healthcare NHS Trust, Wycombe Hospital , Queen Alexandra Road, High Wycombe HP11 2TT , UK 38 Ashford & St Peter's Hospitals NHS Foundation Trust, St Peter's Hospital , Guildford Road, Chertsey KT16 0PZ , UK 39 Burton Hospitals NHS Foundation Trust, Queen's Hospital , Belvedere Road, Burton upon Trent DE13 0RB , UK 40 Barking, Havering and Redbridge University Hosp (...truncated)


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Heather J. Cordell, Younghun Han, George F. Mells, Yafang Li, Gideon M. Hirschfield, Casey S. Greene, Gang Xie, Brian D. Juran, Dakai Zhu, David C. Qian, James A. B. Floyd, Katherine I. Morley, Daniele Prati, Ana Lleo, Daniele Cusi, M. Eric Gershwin, Carl A. Anderson, Konstantinos N. Lazaridis, Pietro Invernizzi, Michael F. Seldin, Richard N. Sandford, Christopher I. Amos, Katherine A. Siminovitch. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways, Nature Communications, 2015, Issue: 6, DOI: 10.1038/ncomms9019