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    Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.

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    Author
    Sarnowski, Chloé
    Chen, Han
    Biggs, Mary L
    Wassertheil-Smoller, Sylvia
    Bressler, Jan
    Irvin, Marguerite R
    Ryan, Kathleen A
    Karasik, David
    Arnett, Donna K
    Cupples, L Adrienne
    Fardo, David W
    Gogarten, Stephanie M
    Heavner, Benjamin D
    Jain, Deepti
    Kang, Hyun Min
    Kooperberg, Charles
    Mainous, Arch G
    Mitchell, Braxton D
    Morrison, Alanna C
    O'Connell, Jeffrey R
    Psaty, Bruce M
    Rice, Kenneth
    Smith, Albert V
    Vasan, Ramachandran S
    Windham, B Gwen
    Kiel, Douglas P
    Murabito, Joanne M
    Lunetta, Kathryn L
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    Date
    2021-07-02
    Journal
    PLoS ONE
    Publisher
    Public Library of Science
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1371/journal.pone.0253611
    Abstract
    Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.
    Keyword
    Genetic Loci
    Genetic Variation
    Hand Strength
    Whole Genome Sequencing
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16135
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0253611
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