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         headline:Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease
         description:Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease. Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.
         datePublished:2018-04-24T00:00:00Z
         dateModified:2018-04-24T00:00:00Z
         pageStart:1
         pageEnd:8
         license:http://creativecommons.org/licenses/by/4.0/
         sameAs:https://doi.org/10.1038/s41467-018-03911-8
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            Genetic association study
            Genetic predisposition to disease
            Medical genomics
            Rare variants
            Science
            Humanities and Social Sciences
            multidisciplinary
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      headline:Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease
      description:Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease. Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.
      datePublished:2018-04-24T00:00:00Z
      dateModified:2018-04-24T00:00:00Z
      pageStart:1
      pageEnd:8
      license:http://creativecommons.org/licenses/by/4.0/
      sameAs:https://doi.org/10.1038/s41467-018-03911-8
      keywords:
         Genetic association study
         Genetic predisposition to disease
         Medical genomics
         Rare variants
         Science
         Humanities and Social Sciences
         multidisciplinary
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            name:Icahn School of Medicine at Mount Sinai
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               name:Wellcome Trust Sanger Institute, Hinxton, UK
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      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
      name:Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
      name:Department of Computational Biology & Bioinformatics, Yale Medical School, Yale University, New Haven, USA
      name:Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA
      name:Department of Medicine, Massachusetts General Hospital, Cardiology Division, Harvard Medical School, Boston, USA
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
      name:Division of Cardiology, Azienda Ospedaliero–Universitaria di Parma, Parma, Italy
      name:Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy
      name:Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
      name:Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany
      name:University of Ottawa Heart Institute, Ottawa, Canada
      name:Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK
      name:Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
      name:Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain
      name:CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain
      name:Facultat de Medicina, Universitat de Vic-Central de Cataluña, Barcelona, Spain
      name:Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, UK
      name:Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, UK
      name:The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA
      name:Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
      name:Department of Public Health and Primary Care, Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, UK
      name:Wellcome Trust Sanger Institute, Hinxton, UK
      name:National Institute of Health Research Blood and Transplant; Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK
      name:Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Boston, USA
      name:Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Boston, USA
      name:Department of Biomedical Informatics, Vanderbilt University, Nashville, USA
      name:Department of Biomedical Informatics, Vanderbilt University, Nashville, USA
      name:Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, USA
      name:Department of Emergency Medicine, Yale University, New Haven, USA
      name:Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, USA
      name:Department of Biomedical & Saint Luke’s Mid America Heart Institute and the Health Informatics, Division of Endocrinology and Metabolism, University of Missouri-Kansas City, Kansas City, USA
      name:Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
      name:The Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, USA
      name:Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, USA
      name:Cardiovascular Health Research Unit, Kaiser Permanente Washington Health Research Institute, Seattle, USA
      name:Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, USA
      name:Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA
      name:The Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, USA
      name:The Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, USA
      name:Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, USA
      name:Center for Non-Communicable Diseases, Karachi, Pakistan
      name:Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
      name:Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA
      name:Department of Medicine, Massachusetts General Hospital, Cardiology Division, Harvard Medical School, Boston, USA
      name:Program in Medical and Population Genetics, Broad Institute, Cambridge, USA

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