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

James P. Davis, Jeroen R. Huyghe, Adam Locke, Anne U. Jackson, Xueling Sim, Heather M. Stringham, Tanya M. Teslovich, Ryan P. Welch, Christian Fuchsberger, Narisu Narisu, Peter S. Chines, Antti J. Kangas, Pasi Soininen, Mika Ala-Korpela, Johanna Kuusisto, Markku Laakso, Michael Boehnke, Karen L. Mohlke

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17 Scopus citations

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.

Original languageEnglish
Article numbere1007079
JournalPLoS genetics
Volume13
Issue number10
DOIs
StatePublished - Oct 2017

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