A1 Refereed original research article in a scientific journal
The impact of low-frequency and rare variants on lipid levels
Authors: Surakka I, Horikoshi M, Magi R, Sarin AP, Mahajan A, Lagou V, Marullo L, Ferreira T, Miraglio B, Timonen S, Kettunen J, Pirinen M, Karjalainen J, Thorleifsson G, Hagg S, Hottenga JJ, Isaacs A, Ladenvall C, Beekman M, Esko T, Ried JS, Nelson CP, Willenborg C, Gustafsson S, Westra HJ, Blades M, de Craen AJM, de Geus EJ, Deelen J, Grallert H, Hamsten A, Havulinna AS, Hengstenberg C, Houwing-Duistermaat JJ, Hypponen E, Karssen LC, Lehtimaki T, Lyssenko V, Magnusson PKE, Mihailov E, Muller-Nurasyid M, Mpindi JP, Pedersen NL, Penninx BWJH, Perola M, Pers TH, Peters A, Rung J, Smit JH, Steinthorsdottir V, Tobin MD, Tsernikova N, van Leeuwen EM, Viikari JS, Willems SM, Willemsen G, Schunkert H, Erdmann J, Samani NJ, Kaprio J, Lind L, Gieger C, Metspalu A, Slagboom PE, Groop L, van Duijn CM, Eriksson JG, Jula A, Salomaa V, Boomsma DI, Power C, Raitakari OT, Ingelsson E, Jarvelin MR, Thorsteinsdottir U, Franke L, Ikonen E, Kallioniemi O, Pietiainen V, Lindgren CM, Stefansson K, Palotie A, McCarthy MI, Morris AP, Prokopenko I, Ripatti S; ENGAGE Consortium
Publisher: NATURE PUBLISHING GROUP
Publication year: 2015
Journal: Nature Genetics
Journal name in source: NATURE GENETICS
Journal acronym: NAT GENET
Volume: 47
Issue: 6
First page : 589
Last page: 597
Number of pages: 9
ISSN: 1061-4036
DOI: https://doi.org/10.1038/ng.3300
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.
