title: International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.
abstract: 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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Academic Department of Medical Genetics, Cambridge University, Cambridge CB2 0QQ, UK.
authors.forename: George F
authors.initials: GF
authors.lastname: Mells
authors.affiliation: Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Department of Genetics, Institute for Quantitative Biomedical Sciences, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Casey S
authors.initials: CS
authors.lastname: Greene
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.affiliation: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Juran
authors.affiliation: Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
authors.forename: Dakai
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Qian
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.|William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: James A B
authors.initials: JA
authors.lastname: Floyd
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.|Institute of Psychiatry, Psychology &Neuroscience, Kings College London, London SE5 8AF, UK.
authors.forename: Katherine I
authors.initials: KI
authors.lastname: Morley
authors.affiliation: Department of Transfusion Medicine and Hematology, Ospedale Alessandro Manzoni, Lecco 23900, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Prati
authors.affiliation: Center for Autoimmune Liver Diseases, IRCCS Instituto Clinico Humanitas, 20089 Rozzano, Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.affiliation: Università degli Studi di Milano, Milan 20129, Italy.|Istituto di Tecnologie Biomediche Consiglio Nazionale delle Ricerche, Via Fratelli Cervi, 93, 20090 Segrate, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: University of California - Davis, Davis, California 95616, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
authors.affiliation: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Lazaridis
authors.affiliation: Center for Autoimmune Liver Diseases, IRCCS Instituto Clinico Humanitas, 20089 Rozzano, Italy.|University of California - Davis, Davis, California 95616, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: University of California - Davis, Davis, California 95616, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.affiliation: Academic Department of Medical Genetics, Cambridge University, Cambridge CB2 0QQ, UK.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sandford
authors.affiliation: Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario M5G 1X5, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1X5.|Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 1X5.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D055106:Genome-Wide Association Study; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000235:genetics*