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 |
Number of pages | 9 |
Journal | Nature Genetics |
Volume | 47 |
Issue number | 6 |
DOIs | |
Publication status | Published - 27 May 2015 |
ASJC Scopus subject areas
- Genetics
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The impact of low-frequency and rare variants on lipid levels. / Surakka, Ida; Horikoshi, Momoko; Mägi, Reedik; Sarin, Antti Pekka; Mahajan, Anubha; Lagou, Vasiliki; Marullo, Letizia; Ferreira, Teresa; Miraglio, Benjamin; Timonen, Sanna; Kettunen, Johannes; Pirinen, Matti; Karjalainen, Juha; Thorleifsson, Gudmar; Hägg, Sara; Hottenga, Jouke Jan; Isaacs, Aaron; Ladenvall, Claes; Beekman, Marian; Esko, Tõnu; Ried, Janina S.; Nelson, Christopher P.; Willenborg, Christina; Gustafsson, Stefan; Westra, Harm Jan; Blades, Matthew; De Craen, Anton J M; De Geus, Eco J.; Deelen, Joris; Grallert, Harald; Hamsten, Anders; Havulinna, Aki S.; Hengstenberg, Christian; Houwing-Duistermaat, Jeanine J.; Hyppönen, Elina; Karssen, Lennart C.; Lehtimäki, Terho; Lyssenko, Valeriya; Magnusson, Patrik K E; Mihailov, Evelin; Müller-Nurasyid, Martina; Mpindi, John Patrick; Pedersen, Nancy L.; Penninx, Brenda W J H; Perola, Markus; Pers, Tune H.; Peters, Annette; Rung, Johan; Smit, Johannes H.; Steinthorsdottir, Valgerdur; Tobin, Martin D.; Tsernikova, Natalia; Van Leeuwen, Elisabeth M.; Viikari, Jorma S.; Willems, Sara M.; Willemsen, Gonneke; Schunkert, Heribert; Erdmann, Jeanette; Samani, Nilesh J.; Kaprio, Jaakko; Lind, Lars; Gieger, Christian; Metspalu, Andres; Eline Slagboom, P.; Groop, Leif; Van Duijn, Cornelia M.; Eriksson, Johan G.; Jula, Antti; Salomaa, Veikko; Boomsma, Dorret I.; Power, Christine; Raitakari, Olli T.; Ingelsson, Erik; Järvelin, Marjo Riitta; Thorsteinsdottir, Unnur; Franke, Lude; Ikonen, Elina; Kallioniemi, Olli; Pietiäinen, Vilja; Lindgren, Cecilia M.; Stefansson, Kari; Palotie, Aarno; McCarthy, Mark I.; Morris, Andrew P.; Prokopenko, Inga; Ripatti, Samuli.
In: Nature Genetics, Vol. 47, No. 6, 27.05.2015, p. 589-597.Research output: Contribution to journal › Article
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 - 2015/5/27
Y1 - 2015/5/27
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 - Article
C2 - 25961943
AN - SCOPUS:84930090376
VL - 47
SP - 589
EP - 597
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 6
ER -