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; Ozren Polasek; Veronique Vitart; Igor Rudan; Alan F. Wright; Stephen S. Rich; Bruce M. Psaty; Ingrid B. Borecki; Patricia M. Kearney; David J. Stott; L. Adrienne Cupples; J. Wouter Jukema; Pim Van Der Harst; Eric J. Sijbrands; Jouke Jan Hottenga; Andre G. Uitterlinden; Morris A. Swertz; Gert Jan B Van Ommen; Paul I W De Bakker; P. Eline Slagboom; Dorret I. Boomsma; Cisca Wijmenga; Cornelia M. Van Duijn; Pieter B T Neerincx; Clara C. Elbers; Pier Francesco Palamara; Itsik Peer; Abdel Abdellaoui; Wigard P. Kloosterman; Mannis Van Oven; Martijn Vermaat; Mingkun Li; Jeroen F J Laros; Mark Stoneking; Peter De Knijff; Manfred Kayser; Jan H. Veldink; Leonard H. Van Den Berg; Heorhiy Byelas; Johan T. Den Dunnen; Martijn Dijkstra; Najaf Amin; K. Joeri Van Der Velde; Jessica Van Setten; Mathijs Kattenberg; Barbera D C Van Schaik; Jan Bot; Isaäc J. Nijman; Hailiang Mei; Vyacheslav Koval; Kai Ye; Eric Wubbo Lameijer; Matthijs H. Moed; Jayne Y. Hehir-Kwa; Robert E. Handsaker; Shamil R. Sunyaev; Mashaal Sohail; Fereydoun Hormozdiari; Tobias Marschall; Alexander Schönhuth; Victor Guryev; H. Eka D Suchiman; Bruce H. Wolffenbuttel; Mathieu Platteel; Steven J. Pitts; Shobha Potluri; David R. Cox; Qibin Li; Yingrui Li; Yuanping Du; Ruoyan Chen; Hongzhi Cao; Ning Li; Sujie Cao; Jun Wang; Jasper A. Bovenberg

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, Ozren Polasek, Veronique Vitart, Igor Rudan, Alan F. Wright, Stephen S. Rich, Bruce M. Psaty, Ingrid B. Borecki, Patricia M. Kearney, David J. Stott, L. Adrienne Cupples, J. Wouter Jukema, Pim Van Der Harst, Eric J. Sijbrands, Jouke Jan Hottenga, Andre G. Uitterlinden, Morris A. Swertz, Gert Jan B Van Ommen, Paul I W De Bakker, P. Eline Slagboom, Dorret I. Boomsma, Cisca Wijmenga, Cornelia M. Van Duijn^*, Pieter B T Neerincx, Clara C. Elbers, Pier Francesco Palamara, Itsik Peer, Abdel Abdellaoui, Wigard P. Kloosterman, Mannis Van Oven, Martijn Vermaat, Mingkun Li, Jeroen F J Laros, Mark Stoneking, Peter De Knijff, Manfred Kayser, Jan H. Veldink, Leonard H. Van Den Berg, Heorhiy Byelas, Johan T. Den Dunnen, Martijn Dijkstra, Najaf Amin, K. Joeri Van Der Velde, Jessica Van Setten, Mathijs Kattenberg, Barbera D C Van Schaik, Jan Bot, Isaäc J. Nijman, Hailiang Mei, Vyacheslav Koval, Kai Ye, Eric Wubbo Lameijer, Matthijs H. Moed, Jayne Y. Hehir-Kwa, Robert E. Handsaker, Shamil R. Sunyaev, Mashaal Sohail, Fereydoun Hormozdiari, Tobias Marschall, Alexander Schönhuth, Victor Guryev, H. Eka D Suchiman, Bruce H. Wolffenbuttel, Mathieu Platteel, Steven J. Pitts, Shobha Potluri, David R. Cox, Qibin Li, Yingrui Li, Yuanping Du, Ruoyan Chen, Hongzhi Cao, Ning Li, Sujie Cao, Jun Wang, Jasper A. Bovenberg

^*Corresponding author for this work

Genome Research and Molecular Bio Medicine

24 Citations (Scopus)

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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 -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.

Original language	English
Article number	6065
Journal	Nature Communications
Volume	6
Number of pages	6
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms7065
Publication status	Published - 2015

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Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levelsFinal published version, 290 KB

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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., ... Bovenberg, J. A. (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

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, Leach, IM, Beekman, M, De Craen, AJM, Uh, HW, 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, Polasek, O, Vitart, V, Rudan, I, Wright, AF, Rich, SS, Psaty, BM, Borecki, IB, Kearney, PM, Stott, DJ, Cupples, LA, Jukema, JW, Van Der Harst, P, Sijbrands, EJ, Hottenga, JJ, Uitterlinden, AG, Swertz, MA, Van Ommen, GJB, De Bakker, PIW, Eline Slagboom, P, Boomsma, DI, Wijmenga, C, Van Duijn, CM, Neerincx, PBT, Elbers, CC, Palamara, PF, Peer, I, Abdellaoui, A, Kloosterman, WP, Van Oven, M, Vermaat, M, Li, M, Laros, JFJ, Stoneking, M, De Knijff, P, Kayser, M, Veldink, JH, Van Den Berg, LH, Byelas, H, Den Dunnen, JT, Dijkstra, M, Amin, N, Van Der Velde, KJ, Van Setten, J, Kattenberg, M, Van Schaik, BDC, Bot, J, Nijman, IJ, Mei, H, Koval, V, Ye, K, Lameijer, EW, Moed, MH, Hehir-Kwa, JY, Handsaker, RE, Sunyaev, SR, Sohail, M, Hormozdiari, F, Marschall, T, Schönhuth, A, Guryev, V, Suchiman, HED, Wolffenbuttel, BH, Platteel, M, Pitts, SJ, Potluri, S, Cox, DR, Li, Q, Li, Y, Du, Y, Chen, R, Cao, H, Li, N, Cao, S, Wang, J & Bovenberg, JA 2015, 'Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels', Nature Communications, vol. 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 -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.",

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 Leach, {Irene Mateo} and Marian Beekman and {De Craen}, {Anton J M} and Uh, {Hae Won} 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 Ozren Polasek and Veronique Vitart and Igor Rudan and Wright, {Alan F.} and Rich, {Stephen S.} and Psaty, {Bruce M.} and Borecki, {Ingrid B.} and Kearney, {Patricia M.} and Stott, {David J.} and Cupples, {L. Adrienne} and Jukema, {J. Wouter} and {Van Der Harst}, Pim and Sijbrands, {Eric J.} and Hottenga, {Jouke Jan} and Uitterlinden, {Andre G.} and Swertz, {Morris A.} and {Van Ommen}, {Gert Jan B} and {De Bakker}, {Paul I W} and {Eline Slagboom}, P. and Boomsma, {Dorret I.} and Cisca Wijmenga and {Van Duijn}, {Cornelia M.} and Neerincx, {Pieter B T} and Elbers, {Clara C.} and Palamara, {Pier Francesco} and Itsik Peer and Abdel Abdellaoui and Kloosterman, {Wigard P.} and {Van Oven}, Mannis and Martijn Vermaat and Mingkun Li and Laros, {Jeroen F J} and Mark Stoneking and {De Knijff}, Peter and Manfred Kayser and Veldink, {Jan H.} and {Van Den Berg}, {Leonard H.} and Heorhiy Byelas and {Den Dunnen}, {Johan T.} and Martijn Dijkstra and Najaf Amin and {Van Der Velde}, {K. Joeri} and {Van Setten}, Jessica and Mathijs Kattenberg and {Van Schaik}, {Barbera D C} and Jan Bot and Nijman, {Isa{\"a}c J.} and Hailiang Mei and Vyacheslav Koval and Kai Ye and Lameijer, {Eric Wubbo} and Moed, {Matthijs H.} and Hehir-Kwa, {Jayne Y.} and Handsaker, {Robert E.} and Sunyaev, {Shamil R.} and Mashaal Sohail and Fereydoun Hormozdiari and Tobias Marschall and Alexander Sch{\"o}nhuth and Victor Guryev and Suchiman, {H. Eka D} and Wolffenbuttel, {Bruce H.} and Mathieu Platteel and Pitts, {Steven J.} and Shobha Potluri and Cox, {David R.} and Qibin Li and Yingrui Li and Yuanping Du and Ruoyan Chen and Hongzhi Cao and Ning Li and Sujie Cao and Jun Wang and Bovenberg, {Jasper A.}",

year = "2015",

doi = "10.1038/ncomms7065",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

}

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 - Leach, Irene Mateo

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 - Polasek, Ozren

AU - Vitart, Veronique

AU - Rudan, Igor

AU - Wright, Alan F.

AU - Rich, Stephen S.

AU - Psaty, Bruce M.

AU - Borecki, Ingrid B.

AU - Kearney, Patricia M.

AU - Stott, David J.

AU - Cupples, L. Adrienne

AU - Jukema, J. Wouter

AU - Van Der Harst, Pim

AU - Sijbrands, Eric J.

AU - Hottenga, Jouke Jan

AU - Uitterlinden, Andre G.

AU - Swertz, Morris A.

AU - Van Ommen, Gert Jan B

AU - De Bakker, Paul I W

AU - Eline Slagboom, P.

AU - Boomsma, Dorret I.

AU - Wijmenga, Cisca

AU - Van Duijn, Cornelia M.

AU - Neerincx, Pieter B T

AU - Elbers, Clara C.

AU - Palamara, Pier Francesco

AU - Peer, Itsik

AU - Abdellaoui, Abdel

AU - Kloosterman, Wigard P.

AU - Van Oven, Mannis

AU - Vermaat, Martijn

AU - Li, Mingkun

AU - Laros, Jeroen F J

AU - Stoneking, Mark

AU - De Knijff, Peter

AU - Kayser, Manfred

AU - Veldink, Jan H.

AU - Van Den Berg, Leonard H.

AU - Byelas, Heorhiy

AU - Den Dunnen, Johan T.

AU - Dijkstra, Martijn

AU - Amin, Najaf

AU - Van Der Velde, K. Joeri

AU - Van Setten, Jessica

AU - Kattenberg, Mathijs

AU - Van Schaik, Barbera D C

AU - Bot, Jan

AU - Nijman, Isaäc J.

AU - Mei, Hailiang

AU - Koval, Vyacheslav

AU - Ye, Kai

AU - Lameijer, Eric Wubbo

AU - Moed, Matthijs H.

AU - Hehir-Kwa, Jayne Y.

AU - Handsaker, Robert E.

AU - Sunyaev, Shamil R.

AU - Sohail, Mashaal

AU - Hormozdiari, Fereydoun

AU - Marschall, Tobias

AU - Schönhuth, Alexander

AU - Guryev, Victor

AU - Suchiman, H. Eka D

AU - Wolffenbuttel, Bruce H.

AU - Platteel, Mathieu

AU - Pitts, Steven J.

AU - Potluri, Shobha

AU - Cox, David R.

AU - Li, Qibin

AU - Li, Yingrui

AU - Du, Yuanping

AU - Chen, Ruoyan

AU - Cao, Hongzhi

AU - Li, Ning

AU - Cao, Sujie

AU - Wang, Jun

AU - Bovenberg, Jasper A.

PY - 2015

Y1 - 2015

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 -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 -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.

U2 - 10.1038/ncomms7065

DO - 10.1038/ncomms7065

M3 - Journal article

C2 - 25751400

AN - SCOPUS:84924363528

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6065

ER -

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

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