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Title:
High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis | Nature Genetics
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.
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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.
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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.
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Genetic association study
Rheumatoid arthritis
Biomedicine
general
Human Genetics
Cancer Research
Agriculture
Gene Function
Animal Genetics and Genomics
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name:Department of Medicine, Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
name:Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
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
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 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
name:Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
name:Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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:HarvardâMassachusetts Institute of Technology Division of Health Sciences and Technology, Boston, USA
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: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, Umeå University, Umeå, Sweden
name:Department of Rheumatology, Umeå University, Umeå, Sweden
name:El Instituto de ParasitologÃa y Biomedicina 'López-Neyra'âConsejo Superior de Investigaciones CientÃficas, Avenida del Conocimiento s/n, Granada, Spain
name:Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
name:Department of Rheumatology, Umeå University, Umeå, Sweden
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: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
name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
name:Department of Medicine, Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
name:The Feinstein Institute for Medical Research, North ShoreâLong 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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