The impact of low-frequency and rare variants on lipid levels

Ida Surakka, Momoko Horikoshi, Reedik Magi, Antti-Pekka Sarin, Anubha Mahajan, Vasiliki Lagou, Letizia Marullo, Teresa Ferreira, Benjamin Miraglio, Sanna Timonen, Johannes Kettunen, Matti Pirinen, Juha Karjalainen, Gudmar Thorleifsson, Sara Hagg, Jouke-Jan Hottenga, Aaron Isaacs, Claes Ladenvall, Marian Beekman, Tonu EskoJanina S. Ried, Christopher P. Nelson, Christina Willenborg, Stefan Gustafsson, Harm-Jan Westra, Matthew Blades, Anton J. M. de Craen, Eco J. de Geus, Joris Deelen, Harald Grallert, Anders Hamsten, Aki S. Havulinna, Christian Hengstenberg, Jeanine J. Houwing-Duistermaat, Elina Hypponen, Lennart C. Karssen, Terho Lehtimaki, Valeriya Lyssenko, Patrik K. E. Magnusson, Evelin Mihailov, Martina Muller-Nurasyid, John-Patrick Mpindi, Nancy L. Pedersen, Brenda W. J. H. Penninx, Markus Perola, Tune H. Pers, Annette Peters, Johan Rung, Johannes H. Smit, Lude Franke, ENGAGE Consortium

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179 Citations (Scopus)

Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

Original languageEnglish
Pages (from-to)589-597
Number of pages9
JournalNature Genetics
Volume47
Issue number6
DOIs
Publication statusPublished - Jun-2015

Keywords

  • GENOME-WIDE ASSOCIATION
  • IN-VITRO
  • HETEROGENEITY
  • EXPRESSION
  • SIALOMUCIN
  • SEQUENCE
  • DISEASE
  • GLUCOSE
  • GENES
  • LIVER

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