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Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes

Author

Listed:
  • Jennifer L. Halford

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Valerie N. Morrill

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Seung Hoan Choi

    (Broad Institute of MIT and Harvard)

  • Sean J. Jurgens

    (Broad Institute of MIT and Harvard
    Amsterdam UMC)

  • Giorgio Melloni

    (Brigham and Women’s Hospital)

  • Nicholas A. Marston

    (Brigham and Women’s Hospital)

  • Lu-Chen Weng

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Victor Nauffal

    (Broad Institute of MIT and Harvard)

  • Amelia W. Hall

    (Broad Institute of MIT and Harvard)

  • Sophia Gunn

    (Boston University School of Public Health)

  • Christina A. Austin-Tse

    (Mass General Brigham Personalized Medicine
    Harvard Medical School
    Massachusetts General Hospital)

  • James P. Pirruccello

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Shaan Khurshid

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Heidi L. Rehm

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Emelia J. Benjamin

    (NHLBI and Boston University’s Framingham Heart Study
    Boston University School of Medicine
    Boston University School of Public Health)

  • Eric Boerwinkle

    (The University of Texas Health Science Center at Houston)

  • Jennifer A. Brody

    (University of Washington)

  • Adolfo Correa

    (University of Mississippi Medical Center)

  • Brandon K. Fornwalt

    (Department of Translational Data Science and Informatics, Geisinger
    Heart Institute, Geisinger
    Department of Radiology, Geisinger)

  • Namrata Gupta

    (Broad Institute of MIT and Harvard)

  • Christopher M. Haggerty

    (Department of Translational Data Science and Informatics, Geisinger
    Heart Institute, Geisinger)

  • Stephanie Harris

    (Massachusetts General Hospital)

  • Susan R. Heckbert

    (University of Washington
    University of Washington)

  • Charles C. Hong

    (University of Maryland School of Medicine)

  • Charles Kooperberg

    (Division of Public Health Sciences, Fred Hutchinson Cancer Center)

  • Henry J. Lin

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Ruth J. F. Loos

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Braxton D. Mitchell

    (University of Maryland School of Medicine
    Baltimore Veterans Administration Medical Center)

  • Alanna C. Morrison

    (The University of Texas Health Science Center at Houston)

  • Wendy Post

    (Johns Hopkins Medicine)

  • Bruce M. Psaty

    (University of Washington
    University of Washington
    University of Washington)

  • Susan Redline

    (Brigham and Women’s Hospital)

  • Kenneth M. Rice

    (University of Washington)

  • Stephen S. Rich

    (University of Virginia)

  • Jerome I. Rotter

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Peter F. Schnatz

    (The Reading Hospital of Tower Health)

  • Elsayed Z. Soliman

    (Wake Forest School of Medicine)

  • Nona Sotoodehnia

    (University of Washington
    Division of Cardiology, Department of Medicine, University of Washington)

  • Eugene K. Wong

    (Massachusetts General Hospital
    Massachusetts General Hospital)

  • Marc S. Sabatine

    (Brigham and Women’s Hospital)

  • Christian T. Ruff

    (Brigham and Women’s Hospital)

  • Kathryn L. Lunetta

    (Boston University School of Public Health)

  • Patrick T. Ellinor

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Steven A. Lubitz

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

Abstract

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P

Suggested Citation

  • Jennifer L. Halford & Valerie N. Morrill & Seung Hoan Choi & Sean J. Jurgens & Giorgio Melloni & Nicholas A. Marston & Lu-Chen Weng & Victor Nauffal & Amelia W. Hall & Sophia Gunn & Christina A. Austi, 2022. "Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32009-5
    DOI: 10.1038/s41467-022-32009-5
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    References listed on IDEAS

    as
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