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    Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

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    Author
    Connell, J.O
    Ryan, K.A
    Parsa, A.
    Date
    2019
    Journal
    Nature communications
    Publisher
    Nature Publishing Group
    Type
    Article
    
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    https://doi.org/10.1038/s41467-019-11576-0
    Abstract
    Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
    Keyword
    Albuminuria
    Genetic Association Studies
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85072119437&doi=10.1038%2fs41467-019-11576-0&partnerID=40&md5=2492aa34c0f972c92c823190bd4d0d08; http://hdl.handle.net/10713/10905
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-019-11576-0
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