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

Samuli Ripatti and colleagues report the results of a genome-wide association study for circulating lipid levels based on 1000 Genomes Project imputation. Their results implicate several new loci, refine the association signals at many established loci and highlight the impact of low-frequency varia...

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Veröffentlicht in:	Nature genetics 2015-06, Vol.47 (6), p.589-597
Hauptverfasser:	Surakka, Ida, Horikoshi, Momoko, Mägi, Reedik, Sarin, Antti-Pekka, Mahajan, Anubha, Lagou, Vasiliki, Marullo, Letizia, Ferreira, Teresa, Miraglio, Benjamin, Timonen, Sanna, Kettunen, Johannes, Pirinen, Matti, Karjalainen, Juha, Thorleifsson, Gudmar, Hägg, Sara, Hottenga, Jouke-Jan, Isaacs, Aaron, Ladenvall, Claes, Beekman, Marian, Esko, Tõnu, Ried, Janina S, Nelson, Christopher P, Willenborg, Christina, Gustafsson, Stefan, Westra, Harm-Jan, Blades, Matthew, de Craen, Anton J M, de Geus, Eco J, Deelen, Joris, Grallert, Harald, Hamsten, Anders, Havulinna, Aki S, Hengstenberg, Christian, Houwing-Duistermaat, Jeanine J, Hyppönen, Elina, Karssen, Lennart C, Lehtimäki, Terho, Lyssenko, Valeriya, Magnusson, Patrik K E, Mihailov, Evelin, Müller-Nurasyid, Martina, Mpindi, John-Patrick, Pedersen, Nancy L, Penninx, Brenda W J H, Perola, Markus, Pers, Tune H, Peters, Annette, Rung, Johan, Smit, Johannes H, Steinthorsdottir, Valgerdur, Tobin, Martin D, Tsernikova, Natalia, van Leeuwen, Elisabeth M, Viikari, Jorma S, Willems, Sara M, Willemsen, Gonneke, Schunkert, Heribert, Erdmann, Jeanette, Samani, Nilesh J, Kaprio, Jaakko, Lind, Lars, Gieger, Christian, Metspalu, Andres, Slagboom, P Eline, Groop, Leif, van Duijn, Cornelia M, Eriksson, Johan G, Jula, Antti, Salomaa, Veikko, Boomsma, Dorret I, Power, Christine, Raitakari, Olli T, Ingelsson, Erik, Järvelin, Marjo-Riitta, Thorsteinsdottir, Unnur, Franke, Lude, Ikonen, Elina, Kallioniemi, Olli, Pietiäinen, Vilja, Lindgren, Cecilia M, Stefansson, Kari, Palotie, Aarno, McCarthy, Mark I, Morris, Andrew P, Prokopenko, Inga, Ripatti, Samuli
Format:	Artikel
Sprache:	eng
Schlagworte:	45 45/43 631/208/205/2138 Agreements Agriculture Animal Genetics and Genomics Biomedicine Cancer Research Cholesterol Clinical Medicine Design Dyslipidemias - genetics Endocrinology and Diabetes Endokrinologi och diabetes Gene Frequency Gene Function Genetic aspects Genetic Loci Genetic variance Genetics Genome-Wide Association Study Health aspects Human Genetics Humans Identification and classification Klinisk medicin Linkage Disequilibrium Lipid metabolism Lipid Metabolism - genetics Lipids Medical and Health Sciences Medicin och hälsovetenskap Mutation, Missense Polymorphism, Single Nucleotide Sequence Analysis, DNA Single nucleotide polymorphisms Studies
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Zusammenfassung:	Samuli Ripatti and colleagues report the results of a genome-wide association study for circulating lipid levels based on 1000 Genomes Project imputation. Their results implicate several new loci, refine the association signals at many established loci and highlight the impact of low-frequency variants on lipid traits. 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.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.3300