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 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

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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 <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 languageEnglish
Article number6065
Number of pages6
JournalNature Communications
Volume6
Early online date9 Mar 2015
DOIs
Publication statusPublished - 9 Mar 2015

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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., ... Genome of the Netherlands Consortium (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