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

I. Surakka; M. Horikoshi; R. Magi; A. Sarin; A. Mahajan; V. Lagou; L. Marullo; T. Ferreira; B. Miraglio; S. Timonen; J. Kettunen; M. Pirinen; J. Karjalainen; G. Thorleifsson; S. Hagg; J.J. Hottenga; A. Isaacs; C. Ladenvall; M. Beekman; T. Esko; J.S. Ried; C.P. Nelson; C. Willenborg; S. Gustafsson; H. Westra; M. Blades; A.J.M. Craen; E.J.C. de Geus; J. Deelen; H. Grallert; A. Hamsten; A.S. Havulinna; C. Hengstenberg; J.J. Houwing-Duistermaat; E. Hypponen; L.C. Karssen; T. Lehtimaki; V. Lyssenko; P.K.E. Magnusson; E. Mihailov; M. Muller-Nurasyid; J. Mpindi; N.L. Pedersen; B.W.J.H. Penninx; M. Perola; T.H. Pers; A. Peters; J. Rung; J.H. Smit; V. Steinthorsdottir; M.D. Tobin; N. Tsernikova; E.M. van Leeuwen; J.S. Viikari; S.M. Willems; G. Willemsen; H. Schunkert; J. Erdmann; N.J. Samani; J. Kaprio; L. Lind; C. Gieger; A. Metspalu; P.E. Slagboom; L. Groop; C.M. van Duijn; J.G. Eriksson; A. Jula; V. Salomaa; D.I. Boomsma; C. Power; O.T. Raitakari; E. Ingelsson; M. Jarvelin; U. Thorsteinsdottir; L. Franke; E. Ikonen; O. Kallioniemi; V. Pietiainen; C.M. Lindgren; K. Stefansson; A. Palotie; M.I. McCarthy; A.P. Morris; I. Prokopenko; S. Ripatti

doi:10.1038/ng.3300

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

I. Surakka, M. Horikoshi, R. Magi, A. Sarin, A. Mahajan, V. Lagou, L. Marullo, T. Ferreira, B. Miraglio, S. Timonen, J. Kettunen, M. Pirinen, J. Karjalainen, G. Thorleifsson, S. Hagg, J.J. Hottenga, A. Isaacs, C. Ladenvall, M. Beekman, T. EskoJ.S. Ried, C.P. Nelson, C. Willenborg, S. Gustafsson, H. Westra, M. Blades, A.J.M. Craen, E.J.C. de Geus, J. Deelen, H. Grallert, A. Hamsten, A.S. Havulinna, C. Hengstenberg, J.J. Houwing-Duistermaat, E. Hypponen, L.C. Karssen, T. Lehtimaki, V. Lyssenko, P.K.E. Magnusson, E. Mihailov, M. Muller-Nurasyid, J. Mpindi, N.L. Pedersen, B.W.J.H. Penninx, M. Perola, T.H. Pers, A. Peters, J. Rung, J.H. Smit, V. Steinthorsdottir, M.D. Tobin, N. Tsernikova, E.M. van Leeuwen, J.S. Viikari, S.M. Willems, G. Willemsen, H. Schunkert, J. Erdmann, N.J. Samani, J. Kaprio, L. Lind, C. Gieger, A. Metspalu, P.E. Slagboom, L. Groop, C.M. van Duijn, J.G. Eriksson, A. Jula, V. Salomaa, D.I. Boomsma, C. Power, O.T. Raitakari, E. Ingelsson, M. Jarvelin, U. Thorsteinsdottir, L. Franke, E. Ikonen, O. Kallioniemi, V. Pietiainen, C.M. Lindgren, K. Stefansson, A. Palotie, M.I. McCarthy, A.P. Morris, I. Prokopenko, S. Ripatti

Biological Psychology

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)	589-597
Journal	Nature Genetics
Volume	47
Issue number	6
DOIs	https://doi.org/10.1038/ng.3300
Publication status	Published - 2015

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PT: J; UT: WOS:000355386500009

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Surakka, I., Horikoshi, M., Magi, R., Sarin, A., Mahajan, A., Lagou, V., Marullo, L., Ferreira, T., Miraglio, B., Timonen, S., Kettunen, J., Pirinen, M., Karjalainen, J., Thorleifsson, G., Hagg, 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.",

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Surakka, I, Horikoshi, M, Magi, R, Sarin, A, Mahajan, A, Lagou, V, Marullo, L, Ferreira, T, Miraglio, B, Timonen, S, Kettunen, J, Pirinen, M, Karjalainen, J, Thorleifsson, G, Hagg, S, Hottenga, JJ, Isaacs, A, Ladenvall, C, Beekman, M, Esko, T, Ried, JS, Nelson, CP, Willenborg, C, Gustafsson, S, Westra, H, Blades, M, Craen, AJM, de Geus, EJC, Deelen, J, Grallert, H, Hamsten, A, Havulinna, AS, Hengstenberg, C, Houwing-Duistermaat, JJ, Hypponen, E, Karssen, LC, Lehtimaki, T, Lyssenko, V, Magnusson, PKE, Mihailov, E, Muller-Nurasyid, M, Mpindi, J, 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, Slagboom, PE, Groop, L, van Duijn, CM, Eriksson, JG, Jula, A, Salomaa, V, Boomsma, DI, Power, C, Raitakari, OT, Ingelsson, E, Jarvelin, M, Thorsteinsdottir, U, Franke, L, Ikonen, E, Kallioniemi, O, Pietiainen, 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, I.

AU - Horikoshi, M.

AU - Magi, R.

AU - Sarin, A.

AU - Mahajan, A.

AU - Lagou, V.

AU - Marullo, L.

AU - Ferreira, T.

AU - Miraglio, B.

AU - Timonen, S.

AU - Kettunen, J.

AU - Pirinen, M.

AU - Karjalainen, J.

AU - Thorleifsson, G.

AU - Hagg, S.

AU - Hottenga, J.J.

AU - Isaacs, A.

AU - Ladenvall, C.

AU - Beekman, M.

AU - Esko, T.

AU - Ried, J.S.

AU - Nelson, C.P.

AU - Willenborg, C.

AU - Gustafsson, S.

AU - Westra, H.

AU - Blades, M.

AU - Craen, A.J.M.

AU - de Geus, E.J.C.

AU - Deelen, J.

AU - Grallert, H.

AU - Hamsten, A.

AU - Havulinna, A.S.

AU - Hengstenberg, C.

AU - Houwing-Duistermaat, J.J.

AU - Hypponen, E.

AU - Karssen, L.C.

AU - Lehtimaki, T.

AU - Lyssenko, V.

AU - Magnusson, P.K.E.

AU - Mihailov, E.

AU - Muller-Nurasyid, M.

AU - Mpindi, J.

AU - Pedersen, N.L.

AU - Penninx, B.W.J.H.

AU - Perola, M.

AU - Pers, T.H.

AU - Peters, A.

AU - Rung, J.

AU - Smit, J.H.

AU - Steinthorsdottir, V.

AU - Tobin, M.D.

AU - Tsernikova, N.

AU - van Leeuwen, E.M.

AU - Viikari, J.S.

AU - Willems, S.M.

AU - Willemsen, G.

AU - Schunkert, H.

AU - Erdmann, J.

AU - Samani, N.J.

AU - Kaprio, J.

AU - Lind, L.

AU - Gieger, C.

AU - Metspalu, A.

AU - Slagboom, P.E.

AU - Groop, L.

AU - van Duijn, C.M.

AU - Eriksson, J.G.

AU - Jula, A.

AU - Salomaa, V.

AU - Boomsma, D.I.

AU - Power, C.

AU - Raitakari, O.T.

AU - Ingelsson, E.

AU - Jarvelin, M.

AU - Thorsteinsdottir, U.

AU - Franke, L.

AU - Ikonen, E.

AU - Kallioniemi, O.

AU - Pietiainen, V.

AU - Lindgren, C.M.

AU - Stefansson, K.

AU - Palotie, A.

AU - McCarthy, M.I.

AU - Morris, A.P.

AU - Prokopenko, I.

AU - Ripatti, S.

N1 - PT: J; UT: WOS:000355386500009

PY - 2015

Y1 - 2015

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 - https://www.scopus.com/pages/publications/84930090376

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

U2 - 10.1038/ng.3300

DO - 10.1038/ng.3300

M3 - Article

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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