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Nature Research, Nature Genetics, 6(47), p. 589-597, 2015

DOI: 10.1038/ng.3300

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

Journal article published in 2015 by Anton J. M. de Craen, Eco J. de Geus ORCID, Elisabeth M. van Leeuwen, Cornelia M. van Duijn, Ida Surakka, Momoko Horikoshi, Antti-Pekka Sarin, Reedik Mägi, Anubha Mahajan, Reedik Magi, Christina Willenborg, Harm-Jan Westra, Vasiliki Lagou, Gudmar Thorleifsson, Sara Hägg and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Data provided by SHERPA/RoMEO

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.