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

Elisabeth M van Leeuwen; Lennart C Karssen; Joris Deelen; Aaron Isaacs; Carolina Medina-Gomez; Hamdi Mbarek; Alexandros Kanterakis; Stella Trompet; Iris Postmus; Niek Verweij; David J van Enckevort; Jennifer E Huffman; Charles C White; Mary F Feitosa; Traci M Bartz; Ani Manichaikul; Peter K Joshi; Gina M Peloso; Patrick Deelen; Freerk van Dijk; Gonneke Willemsen; Eco J de Geus; Yuri Milaneschi; Brenda W J H Penninx; Laurent C Francioli; Androniki Menelaou; Sara L Pulit; Fernando Rivadeneira; Albert Hofman; Ben A Oostra; Oscar H Franco; Irene Mateo Leach; Marian Beekman; Anton J M de Craen; Hae-Won Uh; Holly Trochet; Lynne J Hocking; David J Porteous; Naveed Sattar; Chris J Packard; Brendan M Buckley; Jennifer A Brody; Joshua C Bis; Jerome I Rotter; Josyf C Mychaleckyj; Harry Campbell; Qing Duan; Leslie A Lange; James F Wilson; Caroline Hayward; Genome of the Netherlands Consortium; C. van Duijn

doi:10.1038/ncomms7065

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

Elisabeth M van Leeuwen, Lennart C Karssen, Joris Deelen, Aaron Isaacs, Carolina Medina-Gomez, Hamdi Mbarek, Alexandros Kanterakis, Stella Trompet, Iris Postmus, Niek Verweij, David J van Enckevort, Jennifer E Huffman, Charles C White, Mary F Feitosa, Traci M Bartz, Ani Manichaikul, Peter K Joshi, Gina M Peloso, Patrick Deelen, Freerk van DijkGonneke Willemsen, Eco J de Geus, Yuri Milaneschi, Brenda W J H Penninx, Laurent C Francioli, Androniki Menelaou, Sara L Pulit, Fernando Rivadeneira, Albert Hofman, Ben A Oostra, Oscar H Franco, Irene Mateo Leach, Marian Beekman, Anton J M de Craen, Hae-Won Uh, Holly Trochet, Lynne J Hocking, David J Porteous, Naveed Sattar, Chris J Packard, Brendan M Buckley, Jennifer A Brody, Joshua C Bis, Jerome I Rotter, Josyf C Mychaleckyj, Harry Campbell, Qing Duan, Leslie A Lange, James F Wilson, Caroline Hayward, Genome of the Netherlands Consortium, C. van Duijn^*

^*Corresponding author for this work

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

Abstract

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 (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

Original language	English
Pages (from-to)	6065
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7065
Publication status	Published - 9 Mar 2015
Externally published	Yes

Keywords

ATP-Binding Cassette Transporters/genetics
Cholesterol/blood
Gene Frequency
Genetic Association Studies
Humans
Mutation, Missense/genetics
Netherlands

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10.1038/ncomms7065Licence: CC BY

Cite this

van Leeuwen, E. M., Karssen, L. C., Deelen, J., Isaacs, A., Medina-Gomez, C., Mbarek, H., Kanterakis, A., Trompet, S., Postmus, I., Verweij, N., van Enckevort, D. J., Huffman, J. E., White, C. C., Feitosa, M. F., Bartz, T. M., Manichaikul, A., Joshi, P. K., Peloso, G. M., Deelen, P., ... van Duijn, C. (2015). Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels. Nature Communications, 6, 6065. https://doi.org/10.1038/ncomms7065

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title = "Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels",

abstract = "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 (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.",

keywords = "ATP-Binding Cassette Transporters/genetics, Cholesterol/blood, Gene Frequency, Genetic Association Studies, Humans, Mutation, Missense/genetics, Netherlands",

author = "{van Leeuwen}, {Elisabeth M} and Karssen, {Lennart C} and Joris Deelen and Aaron Isaacs and Carolina Medina-Gomez and Hamdi Mbarek and Alexandros Kanterakis and Stella Trompet and Iris Postmus and Niek Verweij and {van Enckevort}, {David J} and Huffman, {Jennifer E} and White, {Charles C} and Feitosa, {Mary F} and Bartz, {Traci M} and Ani Manichaikul and Joshi, {Peter K} and Peloso, {Gina M} and Patrick Deelen and {van Dijk}, Freerk and Gonneke Willemsen and {de Geus}, {Eco J} and Yuri Milaneschi and Penninx, {Brenda W J H} and Francioli, {Laurent C} and Androniki Menelaou and Pulit, {Sara L} and Fernando Rivadeneira and Albert Hofman and Oostra, {Ben A} and Franco, {Oscar H} and {Mateo Leach}, Irene and Marian Beekman and {de Craen}, {Anton J M} and Hae-Won Uh and Holly Trochet and Hocking, {Lynne J} and Porteous, {David J} and Naveed Sattar and Packard, {Chris J} and Buckley, {Brendan M} and Brody, {Jennifer A} and Bis, {Joshua C} and Rotter, {Jerome I} and Mychaleckyj, {Josyf C} and Harry Campbell and Qing Duan and Lange, {Leslie A} and Wilson, {James F} and Caroline Hayward and {Genome of the Netherlands Consortium} and {van Duijn}, C.",

year = "2015",

month = mar,

day = "9",

doi = "10.1038/ncomms7065",

language = "English",

volume = "6",

pages = "6065",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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van Leeuwen, EM, Karssen, LC, Deelen, J, Isaacs, A, Medina-Gomez, C, Mbarek, H, Kanterakis, A, Trompet, S, Postmus, I, Verweij, N, van Enckevort, DJ, Huffman, JE, White, CC, Feitosa, MF, Bartz, TM, Manichaikul, A, Joshi, PK, Peloso, GM, Deelen, P, van Dijk, F, Willemsen, G, de Geus, EJ, Milaneschi, Y, Penninx, BWJH, Francioli, LC, Menelaou, A, Pulit, SL, Rivadeneira, F, Hofman, A, Oostra, BA, Franco, OH, Mateo Leach, I, Beekman, M, de Craen, AJM, Uh, H-W, Trochet, H, Hocking, LJ, Porteous, DJ, Sattar, N, Packard, CJ, Buckley, BM, Brody, JA, Bis, JC, Rotter, JI, Mychaleckyj, JC, Campbell, H, Duan, Q, Lange, LA, Wilson, JF, Hayward, C, Genome of the Netherlands Consortium & van Duijn, C 2015, 'Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels', Nature Communications, vol. 6, pp. 6065. https://doi.org/10.1038/ncomms7065

TY - JOUR

T1 - Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

AU - van Leeuwen, Elisabeth M

AU - Karssen, Lennart C

AU - Deelen, Joris

AU - Isaacs, Aaron

AU - Medina-Gomez, Carolina

AU - Mbarek, Hamdi

AU - Kanterakis, Alexandros

AU - Trompet, Stella

AU - Postmus, Iris

AU - Verweij, Niek

AU - van Enckevort, David J

AU - Huffman, Jennifer E

AU - White, Charles C

AU - Feitosa, Mary F

AU - Bartz, Traci M

AU - Manichaikul, Ani

AU - Joshi, Peter K

AU - Peloso, Gina M

AU - Deelen, Patrick

AU - van Dijk, Freerk

AU - Willemsen, Gonneke

AU - de Geus, Eco J

AU - Milaneschi, Yuri

AU - Penninx, Brenda W J H

AU - Francioli, Laurent C

AU - Menelaou, Androniki

AU - Pulit, Sara L

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Oostra, Ben A

AU - Franco, Oscar H

AU - Mateo Leach, Irene

AU - Beekman, Marian

AU - de Craen, Anton J M

AU - Uh, Hae-Won

AU - Trochet, Holly

AU - Hocking, Lynne J

AU - Porteous, David J

AU - Sattar, Naveed

AU - Packard, Chris J

AU - Buckley, Brendan M

AU - Brody, Jennifer A

AU - Bis, Joshua C

AU - Rotter, Jerome I

AU - Mychaleckyj, Josyf C

AU - Campbell, Harry

AU - Duan, Qing

AU - Lange, Leslie A

AU - Wilson, James F

AU - Hayward, Caroline

AU - Genome of the Netherlands Consortium

AU - van Duijn, C.

PY - 2015/3/9

Y1 - 2015/3/9

N2 - 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 (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

AB - 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 (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

KW - ATP-Binding Cassette Transporters/genetics

KW - Cholesterol/blood

KW - Gene Frequency

KW - Genetic Association Studies

KW - Humans

KW - Mutation, Missense/genetics

KW - Netherlands

U2 - 10.1038/ncomms7065

DO - 10.1038/ncomms7065

M3 - Article

C2 - 25751400

SN - 2041-1723

VL - 6

SP - 6065

JO - Nature Communications

JF - Nature Communications

ER -