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    Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

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    Author
    Perry, James A.
    CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
    EPIC-CVD Consortium
    ExomeBP Consortium
    Global Lipids Genetic Consortium
    GoT2D Genes Consortium
    InterAct
    ReproGen Consortium
    T2D-Genes Consortium
    The MAGIC Investigators
    Date
    2019
    Journal
    Nature Genetics
    Publisher
    Nature Publishing Group
    Type
    Article
    
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    https://doi.org/10.1038/s41588-018-0334-2
    Abstract
    Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants. © 2019, The Author(s)
    Sponsors
    This work was primarily supported through funding from the National Institute of Health (NIH): 1K99HL130580, R01-DK089256, 2R01HD057194, U01HG007416, R01DK101855, T32 HL007055, KL2TR001109; and the American Heart Association (AHA): 13POST16500011 and 13GRNT16490017. Co-author Y. Jia recently passed away while this work was in process. This study was completed as part of the Genetic Investigation of ANtropometric Traits (GIANT) Consortium. This research has been conducted using the UK Biobank resource. A full list of acknowledgements is provided in the Supplementary Data 18.
    Keyword
    Genetic Association Studies
    Genetic Research
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85061697378&doi=10.1038%2fs41588-018-0334-2&partnerID=40&md5=d5ceef119f9dfdbae24734b379330b7b; http://hdl.handle.net/10713/11013
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41588-018-0334-2
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