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         headline:Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis
         description:Carl Anderson and colleagues report dense genotyping, using the Immunochip array, of 2,861 primary biliary cirrhosis (PBC) cases and 8,514 controls. They identify three loci newly associated with PBC, and their fine-mapping of previous susceptibility loci identifies five regions with multiple independent common, low-frequency and rare variant associations. 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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            address:
               name:Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Luke Jostins
      affiliation:
            name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
            address:
               name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
               type:PostalAddress
            type:Organization
      name:Heather J Cordell
      affiliation:
            name:Institute of Human Genetics, Newcastle University
            address:
               name:Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
               type:PostalAddress
            type:Organization
      name:Samantha J Ducker
      affiliation:
            name:Institute of Cellular Medicine, Medical School, Newcastle University
            address:
               name:Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
               type:PostalAddress
            type:Organization
      name:Darren B Day
      affiliation:
            name:Cambridge University
            address:
               name:Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Michael A Heneghan
      affiliation:
            name:Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
            address:
               name:Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.,
               type:PostalAddress
            type:Organization
      name:James M Neuberger
      affiliation:
            name:The Liver Unit, Queen Elizabeth Hospital
            address:
               name:The Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
               type:PostalAddress
            type:Organization
      name:Peter T Donaldson
      affiliation:
            name:Institute of Cellular Medicine, Medical School, Newcastle University
            address:
               name:Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
               type:PostalAddress
            type:Organization
      name:Andrew J Bathgate
      affiliation:
            name:Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh
            address:
               name:Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
               type:PostalAddress
            type:Organization
      name:Andrew Burroughs
      affiliation:
            name:Royal Free Campus, University College London Medical School
            address:
               name:Hepatology Department, Royal Free Campus, University College London Medical School, London, UK
               type:PostalAddress
            type:Organization
      name:Mervyn H Davies
      affiliation:
            name:The Liver Unit, St James's University Hospital
            address:
               name:The Liver Unit, St James's University Hospital, Leeds, UK
               type:PostalAddress
            type:Organization
      name:David E Jones
      affiliation:
            name:Institute of Cellular Medicine, Medical School, Newcastle University
            address:
               name:Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
               type:PostalAddress
            type:Organization
      name:Graeme J Alexander
      affiliation:
            name:Cambridge University Hospitals National Health Service (NHS) Foundation Trust
            address:
               name:Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Jeffrey C Barrett
      affiliation:
            name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
            address:
               name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
               type:PostalAddress
            type:Organization
      name:Richard N Sandford
      affiliation:
            name:Cambridge University
            address:
               name:Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Carl A Anderson
      affiliation:
            name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
            address:
               name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
      name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
      name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
      name:Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
      name:Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK
      name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
      name:Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
      name:Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
      name:Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
      name:Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.,
      name:The Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
      name:Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
      name:Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
      name:Hepatology Department, Royal Free Campus, University College London Medical School, London, UK
      name:The Liver Unit, St James's University Hospital, Leeds, UK
      name:Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
      name:Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK
      name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
      name:Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
      name:Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
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