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

Ida Surakka; Momoko Horikoshi; Reedik Mägi; Antti-Pekka Sarin; Anubha Mahajan; Vasiliki Lagou; Letizia Marullo; Teresa Ferreira; Benjamin Miraglio; Sanna Timonen; Johannes Kettunen; Matti Pirinen; Juha Karjalainen; Gudmar Thorleifsson; Sara Hägg; Jouke-Jan Hottenga; Aaron Isaacs; Claes Ladenvall; Marian Beekman; Tõnu Esko; Janina 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 Hyppönen; Lennart C Karssen; Terho Lehtimäki; Valeriya Lyssenko; Patrik K E Magnusson; Evelin Mihailov; Martina Müller-Nurasyid; John-Patrick Mpindi; Nancy L Pedersen; Brenda W J H Penninx; Markus Perola; Tune H Pers; Annette Peters; Johan Rung; Johannes H Smit; Valgerdur Steinthorsdottir; Martin D Tobin; Natalia Tsernikova; Elisabeth M van Leeuwen; Jorma S Viikari; Sara M Willems; Gonneke Willemsen; Heribert Schunkert; Jeanette Erdmann; Nilesh J Samani; Jaakko Kaprio; Lars Lind; Christian Gieger; Andres Metspalu; P Eline Slagboom; Leif Groop; Cornelia M van Duijn; Johan G Eriksson; Antti Jula; Veikko Salomaa; Dorret I Boomsma; Christine Power; Olli T Raitakari; Erik Ingelsson; Marjo-Riitta Järvelin; Unnur Thorsteinsdottir; Lude Franke; Elina Ikonen; Olli Kallioniemi; Vilja Pietiäinen; Cecilia M Lindgren; Kari Stefansson; Aarno Palotie; Mark I McCarthy; Andrew P Morris; Inga Prokopenko; Samuli Ripatti; ENGAGE Consortium

doi:10.1038/ng.3300

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

Journal article

Peer reviewed

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

Ida Surakka, Momoko Horikoshi, Reedik Mägi, Antti-Pekka Sarin, Anubha Mahajan, Vasiliki Lagou, Letizia Marullo, Teresa Ferreira, Benjamin Miraglio, Sanna Timonen, …

Nature genetics, Vol.47(6), pp.589-597

01/06/2015

DOI: https://doi.org/10.1038/ng.3300

PMID: 25961943

Abstract

Dyslipidemias - genetics

Gene Frequency

Genetic Loci

Genome-Wide Association Study

Humans

Linkage Disequilibrium

Lipid Metabolism - genetics

Mutation, Missense

Polymorphism, Single Nucleotide

Sequence Analysis, DNA

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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Title: The impact of low-frequency and rare variants on lipid levels
Creators: Ida Surakka - Institute for Molecular Medicine Finland
Momoko Horikoshi - University of Oxford
Reedik Mägi - University of Tartu
Antti-Pekka Sarin - University of Helsinki
Anubha Mahajan - Wellcome Centre for Human Genetics
Vasiliki Lagou - Wellcome Centre for Human Genetics
Letizia Marullo - University of Ferrara
Teresa Ferreira - Wellcome Centre for Human Genetics
Benjamin Miraglio - Institute for Molecular Medicine Finland
Sanna Timonen - Institute for Molecular Medicine Finland
Johannes Kettunen - University of Helsinki
Matti Pirinen - Institute for Molecular Medicine Finland
Juha Karjalainen - University Medical Center Groningen
Gudmar Thorleifsson - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Sara Hägg - Karolinska Institutet
Jouke-Jan Hottenga - Department of Biological Psychology, EMGO Institute for Health and Care Research, VU University and VU University Medical Center, Amsterdam, the Netherlands
Aaron Isaacs - Erasmus MC
Claes Ladenvall - Lund University
Marian Beekman - Leiden University Medical Center
Tõnu Esko - University of Tartu
Janina S Ried - Helmholtz Zentrum München
Christopher P Nelson - University of Leicester
Christina Willenborg - University of Lübeck
Stefan Gustafsson - Karolinska Institutet
Harm-Jan Westra - University of Groningen
Matthew Blades - Medical Research Council
Anton J M de Craen - Leiden University Medical Center
Eco J de Geus - EMGO Institute for Health and Care Research
Joris Deelen - Leiden University Medical Center
Harald Grallert - Helmholtz Zentrum München
Anders Hamsten - Karolinska Institutet
Aki S Havulinna - Finnish Institute for Health and Welfare
Christian Hengstenberg - Technical University of Munich
Jeanine J Houwing-Duistermaat - Leiden University Medical Center
Elina Hyppönen - UCL Australia
Lennart C Karssen - Erasmus MC
Terho Lehtimäki - Fimlab
Valeriya Lyssenko - Lund University
Patrik K E Magnusson - Karolinska Institutet
Evelin Mihailov - University of Tartu
Martina Müller-Nurasyid - 1] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Munich Heart Alliance, Munich, Germany. Department of Medicine I, University Hospital Großhadern, Ludwig Maximilians Universität, Munich, Germany. Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians Universität, Munich, Germany
John-Patrick Mpindi - Institute for Molecular Medicine Finland
Nancy L Pedersen - Karolinska Institutet
Brenda W J H Penninx - Amsterdam UMC Location VUmc
Markus Perola - University of Tartu
Tune H Pers - Boston Children's Hospital
Annette Peters - Helmholtz Zentrum München
Johan Rung - European Bioinformatics Institute
Johannes H Smit - Amsterdam UMC Location VUmc
Valgerdur Steinthorsdottir - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Martin D Tobin - University of Leicester
Natalia Tsernikova - University of Tartu
Elisabeth M van Leeuwen - Erasmus MC
Jorma S Viikari - University of Turku
Sara M Willems - Erasmus MC
Gonneke Willemsen - EMGO Institute for Health and Care Research
Heribert Schunkert - Technical University of Munich
Jeanette Erdmann - University of Lübeck
Nilesh J Samani - University of Leicester
Jaakko Kaprio - Finnish Institute for Health and Welfare
Lars Lind - Uppsala University Hospital
Christian Gieger - Helmholtz Zentrum München
Andres Metspalu - University of Tartu
P Eline Slagboom - Leiden University Medical Center
Leif Groop - Skåne University Hospital
Cornelia M van Duijn - Erasmus MC
Johan G Eriksson - Finnish Institute for Health and Welfare
Antti Jula - Finnish Institute for Health and Welfare
Veikko Salomaa - Finnish Institute for Health and Welfare
Dorret I Boomsma - EMGO Institute for Health and Care Research
Christine Power - UCL Australia
Olli T Raitakari - University of Turku
Erik Ingelsson - Science for Life Laboratory
Marjo-Riitta Järvelin - Oulu University Hospital
Unnur Thorsteinsdottir - University of Iceland
Lude Franke - University of Groningen
Elina Ikonen - University of Helsinki
Olli Kallioniemi - Institute for Molecular Medicine Finland
Vilja Pietiäinen - Institute for Molecular Medicine Finland
Cecilia M Lindgren - Broad Institute
Kari Stefansson - University of Iceland
Aarno Palotie - Broad Institute
Mark I McCarthy - Oxford Centre for Diabetes, Endocrinology and Metabolism
Andrew P Morris - University of Tartu
Inga Prokopenko - Hammersmith Hospital
Samuli Ripatti - University of Helsinki
ENGAGE Consortium
Publication Details: Nature genetics, Vol.47(6), pp.589-597
Date published: 01/06/2015
Grant note: WT090532 / Wellcome Trust 069224 / Wellcome Trust Wellcome Trust British Heart Foundation G0902313 / Medical Research Council 064890 / Wellcome Trust 098017 / Wellcome Trust 076113 / Wellcome Trust
Identifiers: 99929061502346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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