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

Elisa Leeuwen, Lennart Karssen, J Deelen, Aaron Isaacs, C Medina-Gomez, H Mbarek, A Kanterakis, S Trompet, I Postmus, N (Niek) Verweij, DJ van Enckevort, JE Huffman, CC White, MF Feitosa, TM Bartz, A Manichaikul, PK Joshi, GM Peloso, P Deelen, Femke DijkG Willemsen, EJ de Geus, Y Milaneschi, BWJH Penninx, LC Francioli, A Menelaou, SL Pulit, Fernando Rivadeneira, Bert Hofman, Ben Oostra, OH Franco Duran, IM Leach, M Beekman, AJM de Craen, HW Uh, H Trochet, LJ Hocking, DJ Porteous, N Sattar, CJ Packard, BM Buckley, JA Brody, JC Bis, JI Rotter, JC Mychaleckyj, H Campbell, Q Duan, LA Lange, JF Wilson, C Hayward, O Polasek, V Vitart, I Rudan, AF Wright, SS Rich, BM Psaty, IB Borecki, PM Kearney, DJ Stott, LA Cupples, JW Jukema, P van der Harst, E.J.G. Sijbrands, JJ (Jouke Jan) Hottenga, André Uitterlinden, MA Swertz, GJB van Ommen, PIW de Bakker, PE (Eline) Slagboom, DI Boomsma, C Wijmenga, Cornelia Duijn

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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 (similar to 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 x 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 (beta(LDL-C) = 0.135, beta(TC) = 0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
Original languageUndefined/Unknown
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

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