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         headline:High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
         description:Jane Worthington and colleagues use a high-density genotyping chip to identify new susceptibility loci for rheumatoid arthritis and examine genetic overlap with other autoimmune diseases. Their results increase the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry and refine the location of many previously identified association signals to single genes. Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
         datePublished:2012-11-11T00:00:00Z
         dateModified:2012-11-11T00:00:00Z
         pageStart:1336
         pageEnd:1340
         sameAs:https://doi.org/10.1038/ng.2462
         keywords:
            Genetic association study
            Rheumatoid arthritis
            Biomedicine
            general
            Human Genetics
            Cancer Research
            Agriculture
            Gene Function
            Animal Genetics and Genomics
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               1546-1718
               1061-4036
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               name:Lars Klareskog
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                     name:Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna
                     address:
                        name:Department of Medicine, Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
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               name:Peter K Gregersen
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                     name:The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System
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                        name:The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, USA
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               name:Jane Worthington
               affiliation:
                     name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre
                     address:
                        name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
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                     name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
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                        name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
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      headline:High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
      description:Jane Worthington and colleagues use a high-density genotyping chip to identify new susceptibility loci for rheumatoid arthritis and examine genetic overlap with other autoimmune diseases. Their results increase the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry and refine the location of many previously identified association signals to single genes. Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
      datePublished:2012-11-11T00:00:00Z
      dateModified:2012-11-11T00:00:00Z
      pageStart:1336
      pageEnd:1340
      sameAs:https://doi.org/10.1038/ng.2462
      keywords:
         Genetic association study
         Rheumatoid arthritis
         Biomedicine
         general
         Human Genetics
         Cancer Research
         Agriculture
         Gene Function
         Animal Genetics and Genomics
      image:
         https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fng.2462/MediaObjects/41588_2012_Article_BFng2462_Fig1_HTML.jpg
      isPartOf:
         name:Nature Genetics
         issn:
            1546-1718
            1061-4036
         volumeNumber:44
         type:
            Periodical
            PublicationVolume
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         name:Nature Publishing Group US
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      author:
            name:Steve Eyre
            affiliation:
                  name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre
                  address:
                     name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
                     type:PostalAddress
                  type:Organization
                  name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
                  address:
                     name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
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            name:John Bowes
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            name:Dorothée Diogo
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                  name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
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            name:Annette Lee
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                  name:The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System
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                     name:The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, USA
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            name:Anne Barton
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                  name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
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            name:Paul Martin
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            name:Alexandra Zhernakova
            affiliation:
                  name:Leiden University Medical Centre
                  address:
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                  name:University Medical Center Groningen and University of Groningen
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            name:Eli Stahl
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            name:Sebastien Viatte
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            name:Kate McAllister
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            name:Christopher I Amos
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            name:Leonid Padyukov
            affiliation:
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            name:Rene E M Toes
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            name:Tom W J Huizinga
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            name:Lars Alfredsson
            affiliation:
                  name:Karolinska Institutet
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                     name:Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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            type:Person
            name:Xinli Hu
            affiliation:
                  name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
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                     name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
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                     name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
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                  name:Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology
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                     name:Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, USA
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            type:Person
            name:Cynthia Sandor
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                  name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
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            name:Paul I W de Bakker
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                  name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
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                  name:University Medical Center Utrecht
                  address:
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                  name:University Medical Center Utrecht
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            name:Sonia Davila
            affiliation:
                  name:Genome Institute of Singapore
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            name:Chiea Chuen Khor
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                  name:Genome Institute of Singapore
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            name:Khai Koon Heng
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            name:Robert Andrews
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            name:Cordelia Langford
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            name:Deborah Symmons
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                  name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
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                     name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
                     type:PostalAddress
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            type:Person
            name:Pat Concannon
            affiliation:
                  name:Center for Public Health Genomics, University of Virginia
                  address:
                     name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
                     type:PostalAddress
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            type:Person
            name:Suna Onengut-Gumuscu
            affiliation:
                  name:Center for Public Health Genomics, University of Virginia
                  address:
                     name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
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            name:Stephen S Rich
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                  name:Center for Public Health Genomics, University of Virginia
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            name:Panos Deloukas
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            name:Miguel A Gonzalez-Gay
            affiliation:
                  name:Hospital Marques de Valdecilla, Instituto de Fundación e Investigación Marqués de Valdecilla
                  address:
                     name:Department of Rheumatology, Hospital Marques de Valdecilla, Instituto de Fundación e Investigación Marqués de Valdecilla, Santander, Spain
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            name:Luis Rodriguez-Rodriguez
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                  name:Hospital Clinico San Carlos
                  address:
                     name:Hospital Clinico San Carlos, Madrid, Spain
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            type:Person
            name:Lisbeth Ärlsetig
            affiliation:
                  name:UmeÃ¥ University
                  address:
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                     type:PostalAddress
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                  name:UmeÃ¥ University
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                     name:Department of Rheumatology, UmeÃ¥ University, UmeÃ¥, Sweden
                     type:PostalAddress
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            type:Person
            name:Javier Martin
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                  name:El Instituto de Parasitología y Biomedicina 'López-Neyra'–Consejo Superior de Investigaciones Científicas, Avenida del Conocimiento s/n
                  address:
                     name:El Instituto de Parasitología y Biomedicina 'López-Neyra'–Consejo Superior de Investigaciones Científicas, Avenida del Conocimiento s/n, Granada, Spain
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                  name:UmeÃ¥ University
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                  name:UmeÃ¥ University
                  address:
                     name:Department of Rheumatology, UmeÃ¥ University, UmeÃ¥, Sweden
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            type:Person
            name:Robert M Plenge
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                  name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
                  address:
                     name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
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                  name:Program in Medical and Population Genetics, Broad Institute
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                     name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
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            type:Person
            name:Soumya Raychaudhuri
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                  name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre
                  address:
                     name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
                     type:PostalAddress
                  type:Organization
                  name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
                  address:
                     name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
                     type:PostalAddress
                  type:Organization
                  name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
                  address:
                     name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
                     type:PostalAddress
                  type:Organization
                  name:Brigham and Women's Hospital, Harvard Medical School
                  address:
                     name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
                     type:PostalAddress
                  type:Organization
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               name:Division of Human Genetics, Genome Institute of Singapore, Singapore
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               name:The Wellcome Trust Sanger Institute, Cambridge, UK
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               name:The Wellcome Trust Sanger Institute, Cambridge, UK
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      name:Deborah Symmons
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            name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre
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               name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
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            name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
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               name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
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            name:Center for Public Health Genomics, University of Virginia
            address:
               name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
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      name:Suna Onengut-Gumuscu
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            name:Center for Public Health Genomics, University of Virginia
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               name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
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               name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
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            name:Hospital Marques de Valdecilla, Instituto de Fundación e Investigación Marqués de Valdecilla
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               name:Department of Rheumatology, Hospital Marques de Valdecilla, Instituto de Fundación e Investigación Marqués de Valdecilla, Santander, Spain
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      name:Luis Rodriguez-Rodriguez
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      name:Lisbeth Ärlsetig
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      name:Javier Martin
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               name:El Instituto de Parasitología y Biomedicina 'López-Neyra'–Consejo Superior de Investigaciones Científicas, Avenida del Conocimiento s/n, Granada, Spain
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               name:Department of Rheumatology, UmeÃ¥ University, UmeÃ¥, Sweden
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      name:Robert M Plenge
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            name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
            address:
               name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
               type:PostalAddress
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            address:
               name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
            name:Program in Medical and Population Genetics, Broad Institute
            address:
               name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Soumya Raychaudhuri
      affiliation:
            name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre
            address:
               name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
               type:PostalAddress
            type:Organization
            name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
            address:
               name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
               type:PostalAddress
            type:Organization
            name:Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School
            address:
               name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
            name:Brigham and Women's Hospital, Harvard Medical School
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               name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
            name:Program in Medical and Population Genetics, Broad Institute
            address:
               name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Lars Klareskog
      affiliation:
            name:Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna
            address:
               name:Department of Medicine, Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
               type:PostalAddress
            type:Organization
      name:Peter K Gregersen
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            name:The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System
            address:
               name:The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, USA
               type:PostalAddress
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      name:Jane Worthington
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            name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre
            address:
               name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
               type:PostalAddress
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            name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre
            address:
               name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
               type:PostalAddress
            type:Organization
      email:[email protected]
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      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
      name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
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      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
      name:Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
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      name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
      name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:University of Texas MD Anderson Cancer Center, Houston, USA
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      name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
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      name:Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
      name:Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
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      name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
      name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
      name:Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands
      name:Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
      name:Division of Human Genetics, Genome Institute of Singapore, Singapore
      name:Division of Human Genetics, Genome Institute of Singapore, Singapore
      name:Division of Human Genetics, Genome Institute of Singapore, Singapore
      name:The Wellcome Trust Sanger Institute, Cambridge, UK
      name:The Wellcome Trust Sanger Institute, Cambridge, UK
      name:The Wellcome Trust Sanger Institute, Cambridge, UK
      name:The Wellcome Trust Sanger Institute, Cambridge, UK
      name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
      name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
      name:Center for Public Health Genomics, University of Virginia, Charlottesville, USA
      name:The Wellcome Trust Sanger Institute, Cambridge, UK
      name:Department of Rheumatology, Hospital Marques de Valdecilla, Instituto de Fundación e Investigación Marqués de Valdecilla, Santander, Spain
      name:Hospital Clinico San Carlos, Madrid, Spain
      name:Department of Public Health and Clinical Medicine, UmeÃ¥ University, UmeÃ¥, Sweden
      name:Department of Rheumatology, UmeÃ¥ University, UmeÃ¥, Sweden
      name:El Instituto de Parasitología y Biomedicina 'López-Neyra'–Consejo Superior de Investigaciones Científicas, Avenida del Conocimiento s/n, Granada, Spain
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      name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
      name:Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
      name:Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
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      name:Department of Medicine, Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
      name:The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, USA
      name:Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
      name:National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
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