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

Cupples, L.; Em, van Leeuwen; van Leeuwen, Elisabeth M.; van Oven, Mannis; Lc, Karssen; van den Berg, Leonard H.; van Setten, Jessica; van Schaik, Barbera D. C.; Deelen, Joris; van Ommen, Gert-Jan B.; Karssen, Lennart C.; Isaacs, Aaron; Medina-gomez, Carolina; Mbarek, Hamdi; Kanterakis, Alexandros; Trompet, Stella; Geus, E.; Postmus, Iris; Verweij, Niek; van Enckevort, David J.; Huffman, Jennifer E.; Dj, van Enckevort; White, Charles C.; Slagboom, P.; Je, Huffman; Feitosa, Mary F.; Bartz, Traci M.; Cc, White; Joshi, Peter K.; Mf, Feitosa; Peloso, Gina M.; Manichaikul, Ani; Tm, Bartz; Dijk, F.; Deelen, Patrick; de Geus, Eco J.; Pk, Joshi; van Dijk, Freerk; Penninx, Brenda W. J. H.; Gm, Peloso; Francioli, Laurent C.; Willemsen, Gonneke; Pulit, Sara L.; Leeuwen, E.; Milaneschi, Yuri; Oostra, Ben A.; Ej, de Geus; Franco, Oscar H.; Menelaou, Androniki; Leach, Irene Mateo; de Craen, Anton J. M.; Bw, Penninx; Rivadeneira, Fernando; Uh, Hae-Won; Lc, Francioli; Hofman, Albert; Hocking, Lynne J.; Porteous, David J.; Packard, Chris J.; Sl, Pulit; Duijn, C.; Buckley, Brendan M.; Beekman, Marian; Brody, Jennifer A.; Bis, Joshua C.; Rotter, Jerome I.; Ba, Oostra; Mychaleckyj, Josyf C.; Trochet, Holly; Oh, Franco; Lange, Leslie A.; Mateo Leach, I.; Wilson, James F.; Sattar, Naveed; van der Harst, Pim; Aj, de Craen; Wright, Alan F.; Hw, Uh; Rich, Stephen S.; Harst, P.; Psaty, Bruce M.; Lj, Hocking; Borecki, Ingrid B.; Kearney, Patricia M.; Dj, Porteous; Stott, David J.; Campbell, Harry; Duan, Qing; Neerincx, Pieter B. T.; Elbers, Clara C.; Cj, Packard; Francesco Palamara, Pier; Pe’er, Itsik; Bm, Buckley; Abdellaoui, Abdel; Hayward, Caroline; Kloosterman, Wigard P.; Ja, Brody; Polasek, Ozren; Vermaat, Martijn; Li, Mingkun; Vitart, Veronique; Jc, Bis; Laros, Jeroen F. J.; Rudan, Igor; Stoneking, Mark; Ji, Rotter; de Knijff, Peter; Kayser, Manfred; Jc, Mychaleckyj; Veldink, Jan H.; Byelas, Heorhiy; den Dunnen, Johan T.; Dijkstra, Martijn; Amin, Najaf; La, Lange; Joeri van der Velde, K.; Kattenberg, Mathijs; Jf, Wilson; Bot, Jan; Adrienne Cupples, L.; Nijman, Isaäc J.; Mei, Hailiang; Koval, Vyacheslav; Ye, Kai; Lameijer, Eric-Wubbo; Moed, Matthijs H.; Hehir-Kwa, Jayne Y.; Handsaker, Robert E.; Sunyaev, Shamil R.; Af, Wright; Craen, A.; Ss, Rich; Sohail, Mashaal; Hormozdiari, Fereydoun; Bm, Psaty; Marschall, Tobias; Schönhuth, Alexander; Ib, Borecki; Guryev, Victor; Suchiman, H. Eka D.; Pm, Kearney; Wolffenbuttel, Bruce H.; Platteel, Mathieu; Dj, Stott; Pitts, Steven J.; Potluri, Shobha; Cox, David R.; Enckevort, D.; Consortium, Genome of The Netherlands; Li, Qibin; Li, Yingrui; Jw, Jukema; Du, Yuanping; Chen, Ruoyan; Cao, Hongzhi; Ej, Sijbrands; Li, Ning; Cao, Sujie; Jj, Hottenga; Wang, Jun; Bovenberg, Jasper A.; Ag, Uitterlinden; Jukema, J. Wouter; Sijbrands, Eric J.; Ma, Swertz; Hottenga, Jouke-Jan; Uitterlinden, Andre G.; Gj, van Ommen; Wouter Jukema, J.; Swertz, Morris A.; Pi, de Bakker; de Bakker, Paul I. W.; Ommen, G.; Eline Slagboom, P.; Boomsma, Dorret I.; Di, Boomsma; Wijmenga, Cisca; van Duijn, Cornelia M.; Bakker, P.; Cm, van Duijn; van Enckevort, Esther

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Joris Deelen
Cupples et al., 2015

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Nature Research, Nature Communications, 1(6), 2015

DOI: 10.1038/ncomms7065

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@article{Cupples2015,
 abstract = {AbstractVariants 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 &lt;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.},
 author = {Cupples, L. and Em, van Leeuwen and van Leeuwen, Elisabeth M. and van Oven, Mannis and Lc, Karssen and van den Berg, Leonard H. and van Setten, Jessica and van Schaik, Barbera D. C. and Deelen, Joris and van Ommen, Gert-Jan B. and Karssen, Lennart C. and Isaacs, Aaron and Medina-gomez, Carolina and Mbarek, Hamdi and Kanterakis, Alexandros and Trompet, Stella and Geus, E. and Postmus, Iris and Verweij, Niek and van Enckevort, David J. and Huffman, Jennifer E. and Dj, van Enckevort and White, Charles C. and Slagboom, P. and Je, Huffman and Feitosa, Mary F. and Bartz, Traci M. and Cc, White and Joshi, Peter K. and Mf, Feitosa and Peloso, Gina M. and Manichaikul, Ani and Tm, Bartz and Dijk, F. and Deelen, Patrick and de Geus, Eco J. and Pk, Joshi and van Dijk, Freerk and Penninx, Brenda W. J. H. and Gm, Peloso and Francioli, Laurent C. and Willemsen, Gonneke and Pulit, Sara L. and Leeuwen, E. and Milaneschi, Yuri and Oostra, Ben A. and Ej, de Geus and Franco, Oscar H. and Menelaou, Androniki and Leach, Irene Mateo and de Craen, Anton J. M. and Bw, Penninx and Rivadeneira, Fernando and Uh, Hae-Won and Lc, Francioli and Hofman, Albert and Hocking, Lynne J. and Porteous, David J. and Packard, Chris J. and Sl, Pulit and Duijn, C. and Buckley, Brendan M. and Beekman, Marian and Brody, Jennifer A. and Bis, Joshua C. and Rotter, Jerome I. and Ba, Oostra and Mychaleckyj, Josyf C. and Trochet, Holly and Oh, Franco and Lange, Leslie A. and Mateo Leach, I. and Wilson, James F. and Sattar, Naveed and van der Harst, Pim and Aj, de Craen and Wright, Alan F. and Hw, Uh and Rich, Stephen S. and Harst, P. and Psaty, Bruce M. and Lj, Hocking and Borecki, Ingrid B. and Kearney, Patricia M. and Dj, Porteous and Stott, David J. and Campbell, Harry and Duan, Qing and Neerincx, Pieter B. T. and Elbers, Clara C. and Cj, Packard and Francesco Palamara, Pier and Pe’er, Itsik and Bm, Buckley and Abdellaoui, Abdel and Hayward, Caroline and Kloosterman, Wigard P. and Ja, Brody and Polasek, Ozren and Vermaat, Martijn and Li, Mingkun and Vitart, Veronique and Jc, Bis and Laros, Jeroen F. J. and Rudan, Igor and Stoneking, Mark and Ji, Rotter and de Knijff, Peter and Kayser, Manfred and Jc, Mychaleckyj and Veldink, Jan H. and Byelas, Heorhiy and den Dunnen, Johan T. and Dijkstra, Martijn and Amin, Najaf and La, Lange and Joeri van der Velde, K. and Kattenberg, Mathijs and Jf, Wilson and Bot, Jan and Adrienne Cupples, L. and Nijman, Isaäc J. and Mei, Hailiang and Koval, Vyacheslav and Ye, Kai and Lameijer, Eric-Wubbo and Moed, Matthijs H. and Hehir-Kwa, Jayne Y. and Handsaker, Robert E. and Sunyaev, Shamil R. and Af, Wright and Craen, A. and Ss, Rich and Sohail, Mashaal and Hormozdiari, Fereydoun and Bm, Psaty and Marschall, Tobias and Schönhuth, Alexander and Ib, Borecki and Guryev, Victor and Suchiman, H. Eka D. and Pm, Kearney and Wolffenbuttel, Bruce H. and Platteel, Mathieu and Dj, Stott and Pitts, Steven J. and Potluri, Shobha and Cox, David R. and Enckevort, D. and Consortium, Genome of The Netherlands and Li, Qibin and Li, Yingrui and Jw, Jukema and Du, Yuanping and Chen, Ruoyan and Cao, Hongzhi and Ej, Sijbrands and Li, Ning and Cao, Sujie and Jj, Hottenga and Wang, Jun and Bovenberg, Jasper A. and Ag, Uitterlinden and Jukema, J. Wouter and Sijbrands, Eric J. and Ma, Swertz and Hottenga, Jouke-Jan and Uitterlinden, Andre G. and Gj, van Ommen and Wouter Jukema, J. and Swertz, Morris A. and Pi, de Bakker and de Bakker, Paul I. W. and Ommen, G. and Eline Slagboom, P. and Boomsma, Dorret I. and Di, Boomsma and Wijmenga, Cisca and van Duijn, Cornelia M. and Bakker, P. and Cm, van Duijn and van Enckevort, Esther},
 doi = {10.1038/ncomms7065},
 journal = {Nature Communications},
 month = {mar},
 title = {Genome of the Netherlands population - specific imputations identify an ABCA6 variant associated with cholesterol levels},
 url = {http://dx.doi.org/10.1038/ncomms7065},
 volume = {6},
 year = {2015}
}

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

Journal article published in 2015 by L. Cupples, van Leeuwen Em, Elisabeth M. van Leeuwen, Mannis van Oven, Karssen Lc, Leonard H. van den Berg, Jessica van Setten, Barbera D. C. van Schaik, Joris Deelen

, Gert-Jan B. van Ommen, Lennart C. Karssen, Aaron Isaacs, Carolina Medina-gomez

, Hamdi Mbarek, Alexandros Kanterakis and other authors. L. Cupples, van Leeuwen Em, Elisabeth M. van Leeuwen, Mannis van Oven, Karssen Lc, Leonard H. van den Berg, Jessica van Setten, Barbera D. C. van Schaik, Joris Deelen

, Gert-Jan B. van Ommen, Lennart C. Karssen, Aaron Isaacs, Carolina Medina-gomez

, Hamdi Mbarek, Alexandros Kanterakis, Stella Trompet, E. Geus, Iris Postmus, Niek Verweij

, David J. van Enckevort, Jennifer E. Huffman, van Enckevort Dj, Charles C. White, P. Slagboom, Huffman Je, Mary F. Feitosa, Traci M. Bartz, White Cc, Peter K. Joshi

, Feitosa Mf, Gina M. Peloso, Ani Manichaikul, Bartz Tm, F. Dijk, Patrick Deelen, Eco J. de Geus, Joshi Pk, Freerk van Dijk, Brenda W. J. H. Penninx, Peloso Gm, Laurent C. Francioli, Gonneke Willemsen, Sara L. Pulit, E. Leeuwen, Yuri Milaneschi, Ben A. Oostra, de Geus Ej, Oscar H. Franco, Androniki Menelaou, Irene Mateo Leach, Anton J. M. de Craen, Penninx Bw, Fernando Rivadeneira, Hae-Won Uh, Francioli Lc, Albert Hofman, Lynne J. Hocking, David J. Porteous, Chris J. Packard, Pulit Sl, C. Duijn, Brendan M. Buckley, Marian Beekman, Jennifer A. Brody, Joshua C. Bis, Jerome I. Rotter, Oostra Ba, Josyf C. Mychaleckyj, Holly Trochet, Franco Oh, Leslie A. Lange, I. Mateo Leach, James F. Wilson, Naveed Sattar, Pim van der Harst, de Craen Aj, Alan F. Wright, Uh Hw, Stephen S. Rich, P. Harst, Bruce M. Psaty, Hocking Lj, Ingrid B. Borecki, Patricia M. Kearney, Porteous Dj, David J. Stott, Harry Campbell, Qing Duan, Pieter B. T. Neerincx, Clara C. Elbers, Packard Cj, Pier Francesco Palamara, Itsik Pe’er, Buckley Bm, Abdel Abdellaoui, Caroline Hayward, Wigard P. Kloosterman, Brody Ja, Ozren Polasek, Martijn Vermaat, Mingkun Li, Veronique Vitart, Bis Jc, Jeroen F. J. Laros, Igor Rudan, Mark Stoneking, Rotter Ji, Peter de Knijff, Manfred Kayser, Mychaleckyj Jc, Jan H. Veldink, Heorhiy Byelas, Johan T. den Dunnen, Martijn Dijkstra, Najaf Amin, Lange La, K. Joeri van der Velde, Mathijs Kattenberg, Wilson Jf, Jan Bot, L. Adrienne Cupples, 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, Wright Af, A. Craen, Rich Ss, Mashaal Sohail, Fereydoun Hormozdiari, Psaty Bm, Tobias Marschall, Alexander Schönhuth, Borecki Ib, Victor Guryev, H. Eka D. Suchiman

, Kearney Pm, Bruce H. Wolffenbuttel, Mathieu Platteel, Stott Dj, Steven J. Pitts, Shobha Potluri, David R. Cox, D. Enckevort, Genome of The Netherlands Consortium, Qibin Li, Yingrui Li, Jukema Jw, Yuanping Du, Ruoyan Chen, Hongzhi Cao, Sijbrands Ej, Ning Li, Sujie Cao, Hottenga Jj, Jun Wang, Jasper A. Bovenberg, Uitterlinden Ag, J. Wouter Jukema, Eric J. Sijbrands, Swertz Ma, Jouke-Jan Hottenga, Andre G. Uitterlinden, van Ommen Gj, J. Wouter Jukema, Morris A. Swertz, de Bakker Pi, Paul I. W. de Bakker, G. Ommen, P. Eline Slagboom

, Dorret I. Boomsma, Boomsma Di, Cisca Wijmenga, Cornelia M. van Duijn, P. Bakker, van Duijn Cm, Esther van Enckevort

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Abstract

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

Abstract

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