Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study

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  • Davis, James P.
    • Affiliation: School of Medicine, Department of Genetics
  • Huyghe, Jeroen R.
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Locke, Adam E.
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Jackson, Anne U.
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Sim, Xueling
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Stringham, Heather M.
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Teslovich, Tanya M.
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Welch, Ryan P.
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Fuchsberger, Christian
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Narisu, Narisu
    • Other Affiliation: National Human Genome Research Institute; National Institutes of Health
  • Chines, Peter S.
    • Other Affiliation: National Human Genome Research Institute; National Institutes of Health
  • Kangas, Antti J.
    • Other Affiliation: Computational Medicine; Faculty of Medicine; University of Oulu and Biocenter Oulu
  • Soininen, Pasi
    • Other Affiliation: NMR Metabolomics Laboratory; School of Pharmacy; University of Eastern Finland
  • Ala-Korpela, Mika
    • Other Affiliation: NMR Metabolomics Laboratory; School of Pharmacy; University of Eastern Finland
  • Kuusisto, Johanna
    • Other Affiliation: Institute of Clinical Medicine; Internal Medicine; University of Eastern Finland and Kuopio University Hospital
  • Laakso, Markku
    • Other Affiliation: Institute of Clinical Medicine; Internal Medicine; University of Eastern Finland and Kuopio University Hospital
  • Boehnke, Michael
    • Other Affiliation: Department of Biostatistics and Center for Statistical Genetics; University of Michigan
  • Mohlke, Karen L.
    • Affiliation: School of Medicine, Department of Genetics
Abstract
  • Lipid and lipoprotein subclasses are associated with metabolic and cardiovascular diseases, yet the genetic contributions to variability in subclass traits are not fully understood. We conducted single-variant and gene-based association tests between 15.1M variants from genome-wide and exome array and imputed genotypes and 72 lipid and lipoprotein traits in 8,372 Finns. After accounting for 885 variants at 157 previously identified lipid loci, we identified five novel signals near established loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG. Four of the signals were identified with a low-frequency (0.005<minor allele frequency [MAF]<0.05) or rare (MAF<0.005) variant, including Arg123His in LCAT. Gene-based associations (P<10−10) support a role for coding variants in LIPC and LIPG with lipoprotein subclass traits. 30 established lipid-associated loci had a stronger association for a subclass trait than any conventional trait. These novel association signals provide further insight into the molecular basis of dyslipidemia and the etiology of metabolic disorders.
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  • Article
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  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 13
Journal issue
  • 10
Page start
  • e1007079
Language
  • English
ISSN
  • 1553-7404
  • 1553-7390

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