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

I Surakka; M Horikoshi; R Magi; AP Sarin; A Mahajan; V Lagou; L Marullo; T Ferreira; B Miraglio; S Timonen; J Kettunen; M Pirinen; J Karjalainen; G Thorleifsson; S Hagg; JJ (Jouke Jan) Hottenga; Aaron Isaacs; C Ladenvall; M Beekman; T Esko; JS Ried; CP Nelson; C Willenborg; S Gustafsson; HJ Westra; M Blades; AJM de Craen; EJ de Geus; J Deelen; H Grallert; A Hamsten; AS Havulinna; C Hengstenberg; JJ Houwing-Duistermaat; E Hypponen; Lennart Karssen; T Lehtimaki; V Lyssenko; PKE Magnusson; E Mihailov; M Muller-Nurasyid; JP Mpindi; NL Pedersen; BWJH Penninx; M Perola; TH Pers; A Peters; J Rung; JH Smit; V Steinthorsdottir; MD Tobin; N Tsernikova; Elisa Leeuwen; JS Viikari; SM Willems; G Willemsen; H Schunkert; J Erdmann; NJ Samani; J Kaprio; L Lind; C Gieger; A Metspalu; PE (Eline) Slagboom; L Groop; Cornelia Duijn; JG Eriksson; A Jula; V Salomaa; DI Boomsma; C Power; OT Raitakari; E Ingelsson; MR Jarvelin; U Thorsteinsdottir; L Franke; E Ikonen; O Kallioniemi; V Pietiainen; CM Lindgren; K Stefansson; A Palotie; MI McCarthy; AP 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, AP Sarin, A Mahajan, V Lagou, L Marullo, T Ferreira, B Miraglio, S Timonen, J Kettunen, M Pirinen, J Karjalainen, G Thorleifsson, S Hagg, JJ (Jouke Jan) Hottenga, Aaron Isaacs, C Ladenvall, M Beekman, T EskoJS Ried, CP Nelson, C Willenborg, S Gustafsson, HJ Westra, M Blades, AJM de Craen, EJ de Geus, J Deelen, H Grallert, A Hamsten, AS Havulinna, C Hengstenberg, JJ Houwing-Duistermaat, E Hypponen, Lennart Karssen, T Lehtimaki, V Lyssenko, PKE Magnusson, E Mihailov, M Muller-Nurasyid, JP Mpindi, NL Pedersen, BWJH Penninx, M Perola, TH Pers, A Peters, J Rung, JH Smit, V Steinthorsdottir, MD Tobin, N Tsernikova, Elisa Leeuwen, JS Viikari, SM Willems, G Willemsen, H Schunkert, J Erdmann, NJ Samani, J Kaprio, L Lind, C Gieger, A Metspalu, PE (Eline) Slagboom, L Groop, Cornelia Duijn, JG Eriksson, A Jula, V Salomaa, DI Boomsma, C Power, OT Raitakari, E Ingelsson, MR Jarvelin, U Thorsteinsdottir, L Franke, E Ikonen, O Kallioniemi, V Pietiainen, CM Lindgren, K Stefansson, A Palotie, MI McCarthy, AP Morris, I Prokopenko, S Ripatti

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

264 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	Undefined/Unknown
Pages (from-to)	589-597
Number of pages	9
Journal	Nature Genetics
Volume	47
Issue number	6
DOIs	https://doi.org/10.1038/ng.3300
Publication status	Published - 2015

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EMC NIHES-01-64-02

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10.1038/ng.3300

Cite this

Surakka, I., Horikoshi, M., Magi, R., Sarin, AP., 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., ... 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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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 = "I Surakka and M Horikoshi and R Magi and AP Sarin and A Mahajan and V Lagou and L Marullo and T Ferreira and B Miraglio and S Timonen and J Kettunen and M Pirinen and J Karjalainen and G Thorleifsson and S Hagg and Hottenga, \{JJ (Jouke Jan)\} and Aaron Isaacs and C Ladenvall and M Beekman and T Esko and JS Ried and CP Nelson and C Willenborg and S Gustafsson and HJ Westra and M Blades and \{de Craen\}, AJM and \{de Geus\}, EJ and J Deelen and H Grallert and A Hamsten and AS Havulinna and C Hengstenberg and JJ Houwing-Duistermaat and E Hypponen and Lennart Karssen and T Lehtimaki and V Lyssenko and PKE Magnusson and E Mihailov and M Muller-Nurasyid and JP Mpindi and NL Pedersen and BWJH Penninx and M Perola and TH Pers and A Peters and J Rung and JH Smit and V Steinthorsdottir and MD Tobin and N Tsernikova and Elisa Leeuwen and JS Viikari and SM Willems and G Willemsen and H Schunkert and J Erdmann and NJ Samani and J Kaprio and L Lind and C Gieger and A Metspalu and Slagboom, \{PE (Eline)\} and L Groop and Cornelia Duijn and JG Eriksson and A Jula and V Salomaa and DI Boomsma and C Power and OT Raitakari and E Ingelsson and MR Jarvelin and U Thorsteinsdottir and L Franke and E Ikonen and O Kallioniemi and V Pietiainen and CM Lindgren and K Stefansson and A Palotie and MI McCarthy and AP Morris and I Prokopenko and S Ripatti",

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Surakka, I, Horikoshi, M, Magi, R, Sarin, AP, 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, HJ, Blades, M, de Craen, AJM, de Geus, EJ, Deelen, J, Grallert, H, Hamsten, A, Havulinna, AS, Hengstenberg, C, Houwing-Duistermaat, JJ, Hypponen, E, Karssen, L, Lehtimaki, T, Lyssenko, V, Magnusson, PKE, Mihailov, E, Muller-Nurasyid, M, Mpindi, JP, Pedersen, NL, Penninx, BWJH, Perola, M, Pers, TH, Peters, A, Rung, J, Smit, JH, Steinthorsdottir, V, Tobin, MD, Tsernikova, N, Leeuwen, E, Viikari, JS, Willems, SM, Willemsen, G, Schunkert, H, Erdmann, J, Samani, NJ, Kaprio, J, Lind, L, Gieger, C, Metspalu, A, Slagboom, PE, Groop, L, Duijn, C, Eriksson, JG, Jula, A, Salomaa, V, Boomsma, DI, Power, C, Raitakari, OT, Ingelsson, E, Jarvelin, MR, 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, AP

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, JJ (Jouke Jan)

AU - Isaacs, Aaron

AU - Ladenvall, C

AU - Beekman, M

AU - Esko, T

AU - Ried, JS

AU - Nelson, CP

AU - Willenborg, C

AU - Gustafsson, S

AU - Westra, HJ

AU - Blades, M

AU - de Craen, AJM

AU - de Geus, EJ

AU - Deelen, J

AU - Grallert, H

AU - Hamsten, A

AU - Havulinna, AS

AU - Hengstenberg, C

AU - Houwing-Duistermaat, JJ

AU - Hypponen, E

AU - Karssen, Lennart

AU - Lehtimaki, T

AU - Lyssenko, V

AU - Magnusson, PKE

AU - Mihailov, E

AU - Muller-Nurasyid, M

AU - Mpindi, JP

AU - Pedersen, NL

AU - Penninx, BWJH

AU - Perola, M

AU - Pers, TH

AU - Peters, A

AU - Rung, J

AU - Smit, JH

AU - Steinthorsdottir, V

AU - Tobin, MD

AU - Tsernikova, N

AU - Leeuwen, Elisa

AU - Viikari, JS

AU - Willems, SM

AU - Willemsen, G

AU - Schunkert, H

AU - Erdmann, J

AU - Samani, NJ

AU - Kaprio, J

AU - Lind, L

AU - Gieger, C

AU - Metspalu, A

AU - Slagboom, PE (Eline)

AU - Groop, L

AU - Duijn, Cornelia

AU - Eriksson, JG

AU - Jula, A

AU - Salomaa, V

AU - Boomsma, DI

AU - Power, C

AU - Raitakari, OT

AU - Ingelsson, E

AU - Jarvelin, MR

AU - Thorsteinsdottir, U

AU - Franke, L

AU - Ikonen, E

AU - Kallioniemi, O

AU - Pietiainen, V

AU - Lindgren, CM

AU - Stefansson, K

AU - Palotie, A

AU - McCarthy, MI

AU - Morris, AP

AU - Prokopenko, I

AU - Ripatti, S

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.

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 -