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Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Author

Listed:
  • Connor A. Emdin

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

  • Amit V. Khera

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

  • Mark Chaffin

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

  • Derek Klarin

    (Harvard Medical School
    Broad Institute
    Harvard Medical School)

  • Pradeep Natarajan

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

  • Krishna Aragam

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

  • Mary Haas

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

  • Alexander Bick

    (Harvard Medical School
    Broad Institute)

  • Seyedeh M. Zekavat

    (Harvard Medical School
    Broad Institute
    Yale University)

  • Akihiro Nomura

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

  • Diego Ardissino

    (Azienda Ospedaliero–Universitaria di Parma
    Associazione per lo Studio Della Trombosi in Cardiologia)

  • James G. Wilson

    (University of Mississippi Medical Center)

  • Heribert Schunkert

    (Deutsches Zentrum für Herz-Kreislauf-Forschung)

  • Ruth McPherson

    (University of Ottawa Heart Institute)

  • Hugh Watkins

    (University of Oxford
    University of Oxford)

  • Roberto Elosua

    (Hospital del Mar Research Institute
    CIBER Enfermedades Cardiovasculares (CIBERCV)
    Universitat de Vic-Central de Cataluña)

  • Matthew J. Bown

    (University of Leicester, and NIHR Leicester Biomedical Research Centre)

  • Nilesh J. Samani

    (University of Leicester, and NIHR Leicester Biomedical Research Centre)

  • Usman Baber

    (Icahn School of Medicine at Mount Sinai)

  • Jeanette Erdmann

    (University of Lübeck)

  • Namrata Gupta

    (Broad Institute)

  • John Danesh

    (University of Cambridge
    Wellcome Trust Sanger Institute
    University of Cambridge)

  • Daniel Chasman

    (Brigham and Women’s Hospital)

  • Paul Ridker

    (Brigham and Women’s Hospital)

  • Joshua Denny

    (Vanderbilt University)

  • Lisa Bastarache

    (Vanderbilt University)

  • Judith H. Lichtman

    (Yale School of Public Health)

  • Gail D’Onofrio

    (Yale University)

  • Jennifer Mattera

    (Yale–New Haven Hospital)

  • John A. Spertus

    (University of Missouri-Kansas City)

  • Wayne H.-H. Sheu

    (Taichung Veterans General Hospital)

  • Kent D. Taylor

    (LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center)

  • Bruce M. Psaty

    (University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • Stephen S. Rich

    (University of Virginia School of Medicine)

  • Wendy Post

    (Johns Hopkins University School of Medicine)

  • Jerome I. Rotter

    (LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center)

  • Yii-Der Ida Chen

    (LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center)

  • Harlan Krumholz

    (Yale–New Haven Hospital)

  • Danish Saleheen

    (Center for Non-Communicable Diseases
    University of Pennsylvania)

  • Stacey Gabriel

    (Broad Institute)

  • Sekar Kathiresan

    (Harvard Medical School
    Harvard Medical School
    Broad Institute)

Abstract

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

Suggested Citation

  • Connor A. Emdin & Amit V. Khera & Mark Chaffin & Derek Klarin & Pradeep Natarajan & Krishna Aragam & Mary Haas & Alexander Bick & Seyedeh M. Zekavat & Akihiro Nomura & Diego Ardissino & James G. Wilso, 2018. "Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03911-8
    DOI: 10.1038/s41467-018-03911-8
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