Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created...

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Autores principales: van Leeuwen, Elisabeth M., Karssen, Lennart C., Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, van Enckevort, David J., Huffman, Jennifer E., White, Charles C., Feitosa, Mary F., Bartz, Traci M., Manichaikul, Ani, Joshi, Peter K., Peloso, Gina M., Deelen, Patrick, van Dijk, Freerk, Willemsen, Gonneke, de Geus, Eco J., Milaneschi, Yuri, Penninx, Brenda W.J.H., Francioli, Laurent C., Menelaou, Androniki, Pulit, Sara L., Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A., Franco, Oscar H., Leach, Irene Mateo, Beekman, Marian, de Craen, Anton J.M., Uh, Hae-Won, Trochet, Holly, Hocking, Lynne J., Porteous, David J., Sattar, Naveed, Packard, Chris J., Buckley, Brendan M., Brody, Jennifer A., Bis, Joshua C., Rotter, Jerome I., Mychaleckyj, Josyf C., Campbell, Harry, Duan, Qing, Lange, Leslie A., Wilson, James F., Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F., Rich, Stephen S., Psaty, Bruce M., Borecki, Ingrid B., Kearney, Patricia M., Stott, David J., Adrienne Cupples, L., Jukema, J. Wouter, van der Harst, Pim, Sijbrands, Eric J., Hottenga, Jouke-Jan, Uitterlinden, Andre G., Swertz, Morris A., van Ommen, Gert-Jan B., de Bakker, Paul I.W., Eline Slagboom, P., Boomsma, Dorret I., Wijmenga, Cisca, van Duijn, Cornelia M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366498/
https://www.ncbi.nlm.nih.gov/pubmed/25751400
http://dx.doi.org/10.1038/ncomms7065
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author van Leeuwen, Elisabeth M.
Karssen, Lennart C.
Deelen, Joris
Isaacs, Aaron
Medina-Gomez, Carolina
Mbarek, Hamdi
Kanterakis, Alexandros
Trompet, Stella
Postmus, Iris
Verweij, Niek
van Enckevort, David J.
Huffman, Jennifer E.
White, Charles C.
Feitosa, Mary F.
Bartz, Traci M.
Manichaikul, Ani
Joshi, Peter K.
Peloso, Gina M.
Deelen, Patrick
van Dijk, Freerk
Willemsen, Gonneke
de Geus, Eco J.
Milaneschi, Yuri
Penninx, Brenda W.J.H.
Francioli, Laurent C.
Menelaou, Androniki
Pulit, Sara L.
Rivadeneira, Fernando
Hofman, Albert
Oostra, Ben A.
Franco, Oscar H.
Leach, Irene Mateo
Beekman, Marian
de Craen, Anton J.M.
Uh, Hae-Won
Trochet, Holly
Hocking, Lynne J.
Porteous, David J.
Sattar, Naveed
Packard, Chris J.
Buckley, Brendan M.
Brody, Jennifer A.
Bis, Joshua C.
Rotter, Jerome I.
Mychaleckyj, Josyf C.
Campbell, Harry
Duan, Qing
Lange, Leslie A.
Wilson, James F.
Hayward, Caroline
Polasek, Ozren
Vitart, Veronique
Rudan, Igor
Wright, Alan F.
Rich, Stephen S.
Psaty, Bruce M.
Borecki, Ingrid B.
Kearney, Patricia M.
Stott, David J.
Adrienne Cupples, L.
Jukema, J. Wouter
van der Harst, Pim
Sijbrands, Eric J.
Hottenga, Jouke-Jan
Uitterlinden, Andre G.
Swertz, Morris A.
van Ommen, Gert-Jan B.
de Bakker, Paul I.W.
Eline Slagboom, P.
Boomsma, Dorret I.
Wijmenga, Cisca
van Duijn, Cornelia M.
author_facet van Leeuwen, Elisabeth M.
Karssen, Lennart C.
Deelen, Joris
Isaacs, Aaron
Medina-Gomez, Carolina
Mbarek, Hamdi
Kanterakis, Alexandros
Trompet, Stella
Postmus, Iris
Verweij, Niek
van Enckevort, David J.
Huffman, Jennifer E.
White, Charles C.
Feitosa, Mary F.
Bartz, Traci M.
Manichaikul, Ani
Joshi, Peter K.
Peloso, Gina M.
Deelen, Patrick
van Dijk, Freerk
Willemsen, Gonneke
de Geus, Eco J.
Milaneschi, Yuri
Penninx, Brenda W.J.H.
Francioli, Laurent C.
Menelaou, Androniki
Pulit, Sara L.
Rivadeneira, Fernando
Hofman, Albert
Oostra, Ben A.
Franco, Oscar H.
Leach, Irene Mateo
Beekman, Marian
de Craen, Anton J.M.
Uh, Hae-Won
Trochet, Holly
Hocking, Lynne J.
Porteous, David J.
Sattar, Naveed
Packard, Chris J.
Buckley, Brendan M.
Brody, Jennifer A.
Bis, Joshua C.
Rotter, Jerome I.
Mychaleckyj, Josyf C.
Campbell, Harry
Duan, Qing
Lange, Leslie A.
Wilson, James F.
Hayward, Caroline
Polasek, Ozren
Vitart, Veronique
Rudan, Igor
Wright, Alan F.
Rich, Stephen S.
Psaty, Bruce M.
Borecki, Ingrid B.
Kearney, Patricia M.
Stott, David J.
Adrienne Cupples, L.
Jukema, J. Wouter
van der Harst, Pim
Sijbrands, Eric J.
Hottenga, Jouke-Jan
Uitterlinden, Andre G.
Swertz, Morris A.
van Ommen, Gert-Jan B.
de Bakker, Paul I.W.
Eline Slagboom, P.
Boomsma, Dorret I.
Wijmenga, Cisca
van Duijn, Cornelia M.
author_sort van Leeuwen, Elisabeth M.
collection PubMed
description Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(−4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (β(LDL-C)=0.135, β(TC)=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
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spelling pubmed-43664982015-04-02 Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels van Leeuwen, Elisabeth M. Karssen, Lennart C. Deelen, Joris Isaacs, Aaron Medina-Gomez, Carolina Mbarek, Hamdi Kanterakis, Alexandros Trompet, Stella Postmus, Iris Verweij, Niek van Enckevort, David J. Huffman, Jennifer E. White, Charles C. Feitosa, Mary F. Bartz, Traci M. Manichaikul, Ani Joshi, Peter K. Peloso, Gina M. Deelen, Patrick van Dijk, Freerk Willemsen, Gonneke de Geus, Eco J. Milaneschi, Yuri Penninx, Brenda W.J.H. Francioli, Laurent C. Menelaou, Androniki Pulit, Sara L. Rivadeneira, Fernando Hofman, Albert Oostra, Ben A. Franco, Oscar H. Leach, Irene Mateo Beekman, Marian de Craen, Anton J.M. Uh, Hae-Won Trochet, Holly Hocking, Lynne J. Porteous, David J. Sattar, Naveed Packard, Chris J. Buckley, Brendan M. Brody, Jennifer A. Bis, Joshua C. Rotter, Jerome I. Mychaleckyj, Josyf C. Campbell, Harry Duan, Qing Lange, Leslie A. Wilson, James F. Hayward, Caroline Polasek, Ozren Vitart, Veronique Rudan, Igor Wright, Alan F. Rich, Stephen S. Psaty, Bruce M. Borecki, Ingrid B. Kearney, Patricia M. Stott, David J. Adrienne Cupples, L. Jukema, J. Wouter van der Harst, Pim Sijbrands, Eric J. Hottenga, Jouke-Jan Uitterlinden, Andre G. Swertz, Morris A. van Ommen, Gert-Jan B. de Bakker, Paul I.W. Eline Slagboom, P. Boomsma, Dorret I. Wijmenga, Cisca van Duijn, Cornelia M. Nat Commun Article Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(−4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (β(LDL-C)=0.135, β(TC)=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR. Nature Pub. Group 2015-03-09 /pmc/articles/PMC4366498/ /pubmed/25751400 http://dx.doi.org/10.1038/ncomms7065 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
van Leeuwen, Elisabeth M.
Karssen, Lennart C.
Deelen, Joris
Isaacs, Aaron
Medina-Gomez, Carolina
Mbarek, Hamdi
Kanterakis, Alexandros
Trompet, Stella
Postmus, Iris
Verweij, Niek
van Enckevort, David J.
Huffman, Jennifer E.
White, Charles C.
Feitosa, Mary F.
Bartz, Traci M.
Manichaikul, Ani
Joshi, Peter K.
Peloso, Gina M.
Deelen, Patrick
van Dijk, Freerk
Willemsen, Gonneke
de Geus, Eco J.
Milaneschi, Yuri
Penninx, Brenda W.J.H.
Francioli, Laurent C.
Menelaou, Androniki
Pulit, Sara L.
Rivadeneira, Fernando
Hofman, Albert
Oostra, Ben A.
Franco, Oscar H.
Leach, Irene Mateo
Beekman, Marian
de Craen, Anton J.M.
Uh, Hae-Won
Trochet, Holly
Hocking, Lynne J.
Porteous, David J.
Sattar, Naveed
Packard, Chris J.
Buckley, Brendan M.
Brody, Jennifer A.
Bis, Joshua C.
Rotter, Jerome I.
Mychaleckyj, Josyf C.
Campbell, Harry
Duan, Qing
Lange, Leslie A.
Wilson, James F.
Hayward, Caroline
Polasek, Ozren
Vitart, Veronique
Rudan, Igor
Wright, Alan F.
Rich, Stephen S.
Psaty, Bruce M.
Borecki, Ingrid B.
Kearney, Patricia M.
Stott, David J.
Adrienne Cupples, L.
Jukema, J. Wouter
van der Harst, Pim
Sijbrands, Eric J.
Hottenga, Jouke-Jan
Uitterlinden, Andre G.
Swertz, Morris A.
van Ommen, Gert-Jan B.
de Bakker, Paul I.W.
Eline Slagboom, P.
Boomsma, Dorret I.
Wijmenga, Cisca
van Duijn, Cornelia M.
Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
title Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
title_full Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
title_fullStr Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
title_full_unstemmed Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
title_short Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
title_sort genome of the netherlands population-specific imputations identify an abca6 variant associated with cholesterol levels
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366498/
https://www.ncbi.nlm.nih.gov/pubmed/25751400
http://dx.doi.org/10.1038/ncomms7065
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