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Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

Author

Listed:
  • Akl C. Fahed

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

  • Minxian Wang

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Julian R. Homburger

    (Color Genomics)

  • Aniruddh P. Patel

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

  • Alexander G. Bick

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

  • Cynthia L. Neben

    (Color Genomics)

  • Carmen Lai

    (Color Genomics)

  • Deanna Brockman

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

  • Anthony Philippakis

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Patrick T. Ellinor

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

  • Christopher A. Cassa

    (Harvard Medical School)

  • Matthew Lebo

    (Partners HealthCare Personalized Medicine)

  • Kenney Ng

    (IBM Research)

  • Eric S. Lander

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    MIT
    Harvard Medical School)

  • Alicia Y. Zhou

    (Color Genomics)

  • Sekar Kathiresan

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

  • Amit V. Khera

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

Abstract

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions — familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background — the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

Suggested Citation

  • Akl C. Fahed & Minxian Wang & Julian R. Homburger & Aniruddh P. Patel & Alexander G. Bick & Cynthia L. Neben & Carmen Lai & Deanna Brockman & Anthony Philippakis & Patrick T. Ellinor & Christopher A. , 2020. "Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17374-3
    DOI: 10.1038/s41467-020-17374-3
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    Cited by:

    1. Akl C. Fahed & Anthony A. Philippakis & Amit V. Khera, 2022. "The potential of polygenic scores to improve cost and efficiency of clinical trials," Nature Communications, Nature, vol. 13(1), pages 1-4, December.
    2. Shaan Khurshid & Julieta Lazarte & James P. Pirruccello & Lu-Chen Weng & Seung Hoan Choi & Amelia W. Hall & Xin Wang & Samuel F. Friedman & Victor Nauffal & Kiran J. Biddinger & Krishna G. Aragam & Pu, 2023. "Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Atlas Khan & Ning Shang & Jordan G. Nestor & Chunhua Weng & George Hripcsak & Peter C. Harris & Ali G. Gharavi & Krzysztof Kiryluk, 2023. "Polygenic risk alters the penetrance of monogenic kidney disease," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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