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

by Boomsma, Dorret I , Eriksson, Johan G , Thorleifsson, Gudmar , Lindgren, Cecilia M , Nelson, Christopher P , Rung, Johan , Pirinen, Matti , Viikari, Jorma S , Morris, Andrew P , Pietiäinen, Vilja , de Craen, Anton J M , Mihailov, Evelin , McCarthy, Mark I , Lyssenko, Valeriya , Erdmann, Jeanette , Kettunen, Johannes , Deelen, Joris , Salomaa, Veikko , Hengstenberg, Christian , Grallert, Harald , Järvelin, Marjo-Riitta , Ingelsson, Erik , Kallioniemi, Olli , Stefansson, Kari , Hottenga, Jouke-Jan , Willemsen, Gonneke , Samani, Nilesh J , Schunkert, Heribert , de Geus, Eco J , Peters, Annette , Miraglio, Benjamin , Tsernikova, Natalia , Isaacs, Aaron , Pedersen, Nancy L , Timonen, Sanna , Esko, Tõnu , Westra, Harm-Jan , Havulinna, Aki S , Lehtimäki, Terho , Ikonen, Elina , Beekman, Marian , Kaprio, Jaakko , Jula, Antti , Raitakari, Olli T , Willems, Sara M , van Leeuwen, Elisabeth M , Mägi, Reedik , Franke, Lude , Ried, Janina S , Ladenvall, Claes , Mpindi, John-Patrick , Tobin, Martin D , Thorsteinsdottir, Unnur , Steinthorsdottir, Valgerdur , Ferreira, Teresa , Lind, Lars , Power, Christine , Karjalainen, Juha , Gustafsson, Stefan , Hägg, Sara , Perola, Markus , Gi

in 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

2015

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2015

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Journal Article

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

Boomsma, Dorret I,

Eriksson, Johan G,

Thorleifsson, Gudmar,

Lindgren, Cecilia M,

Nelson, Christopher P,

Rung, Johan,

Pirinen, Matti,

Viikari, Jorma S,

Morris, Andrew P,

Pietiäinen, Vilja,

de Craen, Anton J M,

Mihailov, Evelin,

McCarthy, Mark I,

Lyssenko, Valeriya,

Erdmann, Jeanette,

Kettunen, Johannes,

Deelen, Joris,

Salomaa, Veikko,

Hengstenberg, Christian,

Grallert, Harald,

Järvelin, Marjo-Riitta,

Ingelsson, Erik,

Kallioniemi, Olli,

Stefansson, Kari,

Hottenga, Jouke-Jan,

Willemsen, Gonneke,

Samani, Nilesh J,

Schunkert, Heribert,

de Geus, Eco J,

Peters, Annette,

Miraglio, Benjamin,

Tsernikova, Natalia,

Isaacs, Aaron,

Pedersen, Nancy L,

Timonen, Sanna,

Esko, Tõnu,

Westra, Harm-Jan,

Havulinna, Aki S,

Lehtimäki, Terho,

Ikonen, Elina,

Beekman, Marian,

Kaprio, Jaakko,

Jula, Antti,

Raitakari, Olli T,

Willems, Sara M,

van Leeuwen, Elisabeth M,

Mägi, Reedik,

Franke, Lude,

Ried, Janina S,

Ladenvall, Claes,

Mpindi, John-Patrick,

Tobin, Martin D,

Thorsteinsdottir, Unnur,

Steinthorsdottir, Valgerdur,

Ferreira, Teresa,

Lind, Lars,

Power, Christine,

Karjalainen, Juha,

Gustafsson, Stefan,

Hägg, Sara,

Perola, Markus,

2015

Overview

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.

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Publisher

Nature Publishing Group US,Nature Publishing Group

Subject

/ 45/43

/ 631/208/205/2138

/ Agreements

/ Agriculture

/ Animal Genetics and Genomics

/ Biomedicine

/ Cancer Research