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

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, 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^*

^*Corresponding author for this work

65 Citations (Scopus)

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
Journal	Nature Genetics
Volume	47
Issue number	6
Pages (from-to)	589-597
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3300
Publication status	Published - 01.01.2015

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10.1038/ng.3300

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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), 589-597. 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.",

author = "Ida Surakka and Momoko Horikoshi and Reedik M{\"a}gi and Sarin, {Antti Pekka} 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 Hottenga, {Jouke Jan} 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 Westra, {Harm Jan} 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 Mpindi, {John Patrick} 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 Tobin, {Martin D.} and Natalia Tsernikova and {Van Leeuwen}, {Elisabeth M.} and Viikari, {Jorma S.} and Willems, {Sara M.} and Gonneke Willemsen and Heribert Schunkert and Jeanette Erdmann and Samani, {Nilesh J.} and Jaakko Kaprio and Lars Lind and Christian Gieger and Andres Metspalu and {Eline Slagboom}, P. and Leif Groop and {Van Duijn}, {Cornelia M.} and Eriksson, {Johan G.} and Antti Jula and Veikko Salomaa and Boomsma, {Dorret I.} and Christine Power and Raitakari, {Olli T.} and Erik Ingelsson and J{\"a}rvelin, {Marjo Riitta} and Unnur Thorsteinsdottir and Lude Franke and Elina Ikonen and Olli Kallioniemi and Vilja Pieti{\"a}inen and Lindgren, {Cecilia M.} and Kari Stefansson and Aarno Palotie and McCarthy, {Mark I.} and Morris, {Andrew P.} and Inga Prokopenko and Samuli Ripatti",

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Surakka, I, Horikoshi, M, Mägi, R, Sarin, AP, Mahajan, A, Lagou, V, Marullo, L, Ferreira, T, Miraglio, B, Timonen, S, Kettunen, J, Pirinen, M, Karjalainen, J, Thorleifsson, G, Hägg, 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, Hyppönen, E, Karssen, LC, Lehtimäki, T, Lyssenko, V, Magnusson, PKE, Mihailov, E, Müller-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, Eline Slagboom, P, Groop, L, Van Duijn, CM, Eriksson, JG, Jula, A, Salomaa, V, Boomsma, DI, Power, C, Raitakari, OT, Ingelsson, E, Järvelin, MR, Thorsteinsdottir, U, Franke, L, Ikonen, E, Kallioniemi, O, Pietiäinen, V, Lindgren, CM, Stefansson, K, Palotie, A, McCarthy, MI, Morris, AP, Prokopenko, I & Ripatti, S 2015, 'The impact of low-frequency and rare variants on lipid levels', Nature Genetics, vol. 47, no. 6, pp. 589-597. 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 - Tobin, Martin D.

AU - Tsernikova, Natalia

AU - Van Leeuwen, Elisabeth M.

AU - Viikari, Jorma S.

AU - Willems, Sara M.

AU - Willemsen, Gonneke

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Samani, Nilesh J.

AU - Kaprio, Jaakko

AU - Lind, Lars

AU - Gieger, Christian

AU - Metspalu, Andres

AU - Eline Slagboom, P.

AU - Groop, Leif

AU - Van Duijn, Cornelia M.

AU - Eriksson, Johan G.

AU - Jula, Antti

AU - Salomaa, Veikko

AU - Boomsma, Dorret I.

AU - Power, Christine

AU - Raitakari, Olli T.

AU - Ingelsson, Erik

AU - Järvelin, Marjo Riitta

AU - Thorsteinsdottir, Unnur

AU - Franke, Lude

AU - Ikonen, Elina

AU - Kallioniemi, Olli

AU - Pietiäinen, Vilja

AU - Lindgren, Cecilia M.

AU - Stefansson, Kari

AU - Palotie, Aarno

AU - McCarthy, Mark I.

AU - Morris, Andrew P.

AU - Prokopenko, Inga

AU - Ripatti, Samuli

PY - 2015/1/1

Y1 - 2015/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84930090376&partnerID=8YFLogxK

U2 - 10.1038/ng.3300

DO - 10.1038/ng.3300

M3 - Journal articles

C2 - 25961943

AN - SCOPUS:84930090376

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

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