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Meta-Analysis
. 2015 Mar 9:6:6065.
doi: 10.1038/ncomms7065.

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

Elisabeth M van Leeuwen  1 Lennart C Karssen  1 Joris Deelen  2 Aaron Isaacs  1 Carolina Medina-Gomez  3 Hamdi Mbarek  4 Alexandros Kanterakis  5 Stella Trompet  6 Iris Postmus  7 Niek Verweij  8 David J van Enckevort  9 Jennifer E Huffman  10 Charles C White  11 Mary F Feitosa  12 Traci M Bartz  13 Ani Manichaikul  14 Peter K Joshi  15 Gina M Peloso  16 Patrick Deelen  5 Freerk van Dijk  5 Gonneke Willemsen  4 Eco J de Geus  4 Yuri Milaneschi  17 Brenda W J H Penninx  17 Laurent C Francioli  18 Androniki Menelaou  18 Sara L Pulit  18 Fernando Rivadeneira  3 Albert Hofman  1 Ben A Oostra  19 Oscar H Franco  1 Irene Mateo Leach  8 Marian Beekman  2 Anton J M de Craen  7 Hae-Won Uh  20 Holly Trochet  10 Lynne J Hocking  21 David J Porteous  22 Naveed Sattar  23 Chris J Packard  24 Brendan M Buckley  25 Jennifer A Brody  26 Joshua C Bis  26 Jerome I Rotter  27 Josyf C Mychaleckyj  14 Harry Campbell  15 Qing Duan  28 Leslie A Lange  28 James F Wilson  15 Caroline Hayward  10 Ozren Polasek  29 Veronique Vitart  10 Igor Rudan  15 Alan F Wright  10 Stephen S Rich  14 Bruce M Psaty  30 Ingrid B Borecki  31 Patricia M Kearney  25 David J Stott  24 L Adrienne Cupples  32 Genome of The Netherlands ConsortiumJ Wouter Jukema  6 Pim van der Harst  8 Eric J Sijbrands  43 Jouke-Jan Hottenga  4 Andre G Uitterlinden  3 Morris A Swertz  5 Gert-Jan B van Ommen  58 Paul I W de Bakker  59 P Eline Slagboom  2 Dorret I Boomsma  60 Cisca Wijmenga  52 Cornelia M van Duijn  1
Collaborators, Affiliations
Meta-Analysis

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

Elisabeth M van Leeuwen et al. Nat Commun. .

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.

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Conflict of interest statement

B.M.P. served on the DSMB of a clinical trial funded by the manufacturer (Zoll Lifecor) and on the Yale Open Data Access Project funded by Johnson & Johnson. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Identified variants for plasma lipid levels.
Distribution of the variants identified by conditional analysis implemented by GCTA to be independently associated with the lipid traits (a) HDL-C (60 variants), (b) LDL-C (142 variants), (c) TC (134 variants) and (d) TG (16 variants)) over MAF bins after meta-analysis of discovery cohorts (black). The histograms also include loci identified in ref. (grey) and ref. (white).

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