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; ENGAGE Consortium; Samuli Ripatti

doi:10.1038/ng.3300

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 EskoJanina 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, ENGAGE Consortium, Samuli Ripatti^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	589-97
Number of pages	9
Journal	Nature Genetics
Volume	47
Issue number	6
DOIs	https://doi.org/10.1038/ng.3300
Publication status	Published - Jun 2015
Externally published	Yes

Keywords

Dyslipidemias/genetics
Gene Frequency
Genetic Loci
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Lipid Metabolism/genetics
Mutation, Missense
Polymorphism, Single Nucleotide
Sequence Analysis, DNA

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Surakka, I., Horikoshi, M., Mägi, R., Sarin, A.-P., Mahajan, A., Lagou, V., Marullo, L., Ferreira, T., Miraglio, B., Timonen, S., Kettunen, J., Pirinen, M., Karjalainen, J., Thorleifsson, G., Hägg, S., Hottenga, J.-J., Isaacs, A., Ladenvall, C., Beekman, M., ... Ripatti, S. (2015). The impact of low-frequency and rare variants on lipid levels. Nature Genetics, 47(6), 589-97. https://doi.org/10.1038/ng.3300

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title = "The impact of low-frequency and rare variants on lipid levels",

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. ",

keywords = "Dyslipidemias/genetics, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Lipid Metabolism/genetics, Mutation, Missense, Polymorphism, Single Nucleotide, Sequence Analysis, DNA",

author = "Ida Surakka and Momoko Horikoshi and Reedik M{\"a}gi and Antti-Pekka Sarin and Anubha Mahajan and Vasiliki Lagou and Letizia Marullo and Teresa Ferreira and Benjamin Miraglio and Sanna Timonen and Johannes Kettunen and Matti Pirinen and Juha Karjalainen and Gudmar Thorleifsson and Sara H{\"a}gg and Jouke-Jan Hottenga and Aaron Isaacs and Claes Ladenvall and Marian Beekman and T{\~o}nu Esko and Ried, {Janina S} and Nelson, {Christopher P} and Christina Willenborg and Stefan Gustafsson and Harm-Jan Westra and Matthew Blades and {de Craen}, {Anton J M} and {de Geus}, {Eco J} and Joris Deelen and Harald Grallert and Anders Hamsten and Havulinna, {Aki S} and Christian Hengstenberg and Houwing-Duistermaat, {Jeanine J} and Elina Hypp{\"o}nen and Karssen, {Lennart C} and Terho Lehtim{\"a}ki and Valeriya Lyssenko and Magnusson, {Patrik K E} and Evelin Mihailov and Martina M{\"u}ller-Nurasyid and John-Patrick Mpindi and Pedersen, {Nancy L} and Penninx, {Brenda W J H} and Markus Perola and Pers, {Tune H} and Annette Peters and Johan Rung and Smit, {Johannes H} and Valgerdur Steinthorsdottir and {ENGAGE Consortium} and Samuli Ripatti",

year = "2015",

month = jun,

doi = "10.1038/ng.3300",

language = "English",

volume = "47",

pages = "589--97",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Surakka, I, Horikoshi, M, Mägi, R, Sarin, A-P, Mahajan, A, Lagou, V, Marullo, L, Ferreira, T, Miraglio, B, Timonen, S, Kettunen, J, Pirinen, M, Karjalainen, J, Thorleifsson, G, Hägg, S, Hottenga, J-J, Isaacs, A, Ladenvall, C, Beekman, M, Esko, T, Ried, JS, Nelson, CP, Willenborg, C, Gustafsson, S, Westra, H-J, Blades, M, de Craen, AJM, de Geus, EJ, Deelen, J, Grallert, H, Hamsten, A, Havulinna, AS, Hengstenberg, C, Houwing-Duistermaat, JJ, Hyppönen, E, Karssen, LC, Lehtimäki, T, Lyssenko, V, Magnusson, PKE, Mihailov, E, Müller-Nurasyid, M, Mpindi, J-P, Pedersen, NL, Penninx, BWJH, Perola, M, Pers, TH, Peters, A, Rung, J, Smit, JH, Steinthorsdottir, V, ENGAGE Consortium & Ripatti, S 2015, 'The impact of low-frequency and rare variants on lipid levels', Nature Genetics, vol. 47, no. 6, pp. 589-97. https://doi.org/10.1038/ng.3300

TY - JOUR

T1 - The impact of low-frequency and rare variants on lipid levels

AU - Surakka, Ida

AU - Horikoshi, Momoko

AU - Mägi, Reedik

AU - Sarin, Antti-Pekka

AU - Mahajan, Anubha

AU - Lagou, Vasiliki

AU - Marullo, Letizia

AU - Ferreira, Teresa

AU - Miraglio, Benjamin

AU - Timonen, Sanna

AU - Kettunen, Johannes

AU - Pirinen, Matti

AU - Karjalainen, Juha

AU - Thorleifsson, Gudmar

AU - Hägg, Sara

AU - Hottenga, Jouke-Jan

AU - Isaacs, Aaron

AU - Ladenvall, Claes

AU - Beekman, Marian

AU - Esko, Tõnu

AU - Ried, Janina S

AU - Nelson, Christopher P

AU - Willenborg, Christina

AU - Gustafsson, Stefan

AU - Westra, Harm-Jan

AU - Blades, Matthew

AU - de Craen, Anton J M

AU - de Geus, Eco J

AU - Deelen, Joris

AU - Grallert, Harald

AU - Hamsten, Anders

AU - Havulinna, Aki S

AU - Hengstenberg, Christian

AU - Houwing-Duistermaat, Jeanine J

AU - Hyppönen, Elina

AU - Karssen, Lennart C

AU - Lehtimäki, Terho

AU - Lyssenko, Valeriya

AU - Magnusson, Patrik K E

AU - Mihailov, Evelin

AU - Müller-Nurasyid, Martina

AU - Mpindi, John-Patrick

AU - Pedersen, Nancy L

AU - Penninx, Brenda W J H

AU - Perola, Markus

AU - Pers, Tune H

AU - Peters, Annette

AU - Rung, Johan

AU - Smit, Johannes H

AU - Steinthorsdottir, Valgerdur

AU - ENGAGE Consortium

AU - Ripatti, Samuli

PY - 2015/6

Y1 - 2015/6

N2 - 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.

AB - 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.

KW - Dyslipidemias/genetics

KW - Gene Frequency

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Humans

KW - Linkage Disequilibrium

KW - Lipid Metabolism/genetics

KW - Mutation, Missense

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, DNA

U2 - 10.1038/ng.3300

DO - 10.1038/ng.3300

M3 - Article

C2 - 25961943

SN - 1061-4036

VL - 47

SP - 589

EP - 597

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

Keywords

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