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Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders

Author

Listed:
  • M. T. Oetjens

    (Geisinger Health System)

  • M. A. Kelly

    (Geisinger Health System)

  • A. C. Sturm

    (Geisinger Health System)

  • C. L. Martin

    (Geisinger Health System)

  • D. H. Ledbetter

    (Geisinger Health System)

Abstract

Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.

Suggested Citation

  • M. T. Oetjens & M. A. Kelly & A. C. Sturm & C. L. Martin & D. H. Ledbetter, 2019. "Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12869-0
    DOI: 10.1038/s41467-019-12869-0
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    Cited by:

    1. Brett M Kroncke & Derek K Smith & Yi Zuo & Andrew M Glazer & Dan M Roden & Jeffrey D Blume, 2020. "A Bayesian method to estimate variant-induced disease penetrance," PLOS Genetics, Public Library of Science, vol. 16(6), pages 1-16, June.
    2. Craig Smail & Bing Ge & Marissa R. Keever-Keigher & Carl Schwendinger-Schreck & Warren A. Cheung & Jeffrey J. Johnston & Cassandra Barrett & Keith Feldman & Ana S. A. Cohen & Emily G. Farrow & Isabell, 2024. "Complex trait associations in rare diseases and impacts on Mendelian variant interpretation," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Karl-Heinz Tomaszowski & Sunetra Roy & Carolina Guerrero & Poojan Shukla & Caezaan Keshvani & Yue Chen & Martina Ott & Xiaogang Wu & Jianhua Zhang & Courtney D. DiNardo & Detlev Schindler & Katharina , 2023. "Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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