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Multicenter Study
. 2014 Sep 16:5:4871.
doi: 10.1038/ncomms5871.

A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

Nicholas J Timpson  1 , Klaudia Walter  2 , Josine L Min  1 , Ioanna Tachmazidou  2 , Giovanni Malerba  3 , So-Youn Shin  1 , Lu Chen  4 , Marta Futema  5 , Lorraine Southam  6 , Valentina Iotchkova  2 , Massimiliano Cocca  2 , Jie Huang  2 , Yasin Memari  2 , Shane McCarthy  2 , Petr Danecek  2 , Dawn Muddyman  2 , Massimo Mangino  7 , Cristina Menni  7 , John R B Perry  8 , Susan M Ring  9 , Amadou Gaye  10 , George Dedoussis  11 , Aliki-Eleni Farmaki  11 , Paul Burton  10 , Philippa J Talmud  5 , Giovanni Gambaro  12 , Tim D Spector  7 , George Davey Smith  1 , Richard Durbin  2 , J Brent Richards  13 , Steve E Humphries  5 , Eleftheria Zeggini  2 , Nicole Soranzo  4 ; UK1OK Consortium Members; UK1OK Consortium Members
Collaborators, Affiliations
Multicenter Study

A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

Nicholas J Timpson et al. Nat Commun. .

Erratum in

  • Erratum: A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans.
    Timpson NJ, Walter K, Min JL, Tachmazidou I, Malerba G, Shin SY, Chen L, Futema M, Southam L, Iotchkova V, Cocca M, Huang J, Memari Y, McCarthy S, Danecek P, Muddyman D, Mangino M, Menni C, Perry JR, Ring SM, Gaye A, Dedoussis G, Farmaki AE, Burton P, Talmud PJ, Gambaro G, Spector TD, Smith GD, Durbin R, Richards JB, Humphries SE, Zeggini E, Soranzo N; UK10K Consortium. Timpson NJ, et al. Nat Commun. 2015 May 12;6:7171. doi: 10.1038/ncomms8171. Nat Commun. 2015. PMID: 25962519 Free PMC article. No abstract available.

Abstract

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.

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Figures

Figure 1
Figure 1. Regional plot of association between genetic variation at the APOC3 locus and plasma TG levels.
The figure is drawn using the UK10K Dalliance Browser. The tracks reported in a indicate (top to bottom): (i) P-value (on the –log10 scale) for association of SNPs in the APOC3 region with TG levels. Symbols are coloured corresponding to r2 to indicate the extent of linkage disequilibrium of each SNP in the region with the index SNPs rs964184 (red square) and the splice variant rs138326449 (blue triangle) marked; (ii) GENCODE genes (from ftp://ngs.sanger.ac.uk/production/gencode/). (b) A cartoon illustrating the genic location of rs138326449 in the context of variable splicing of the APOC3 gene.
Figure 2
Figure 2. Association of lipid levels with rs138326449 at APOC3.
Boxplots of associations between rs138326449 and TG, VLDL and HDL levels are shown as a function of carriage of allele A. Plots for HDL and TC are shown in Supplementary Fig. 2. P values indicate evidence for a linear relationship between lipid sub-fraction level and genotype (assuming an additive model). Box edges indicate the interquartile range (IQR; central line indicating the 50th centile) with the whisker indicating the lowest and highest daya still within 1.5 IQR of respective quartiles.
See this image and copyright information in PMC

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