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

Nicholas J Timpson,Cristina Menni,Shane Mccarthy,Valentina Iotchkova,Mangino Massimo,Massimo Mangino,Petr Danecek,Massimiliano Cocca,Marta Futema,Josine L Min,Susan M Ring,Philippa J Talmud,Klaudia Walter,George Davey Smith,Yasin Memari,Jie Huang,Richard Durbin,John R B Perry,George Dedoussis,Nicole Soranzo,Giovanni Malerba,Giovanni Gambaro,Steve E Humphries,Lorraine Southam,Dawn Muddyman,Eleftheria Zeggini,Lu Chen,Ioanna Tachmazidou,Tim D Spector,J Brent Richards ,Paul R Burton ,Aliki‐Eleni Farmaki ,Amadou Thierno Gaye ,So–Youn Shin

doi:10.1038/ncomms5871

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.

Highlights

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects
Genome-wide studies of common genetic variation and its contribution to commonly measured lipid moieties have been successful in identifying a large number of associated loci[2,3]; the aggregate contribution of all of these confirmed common variants accounts currently for only about 10–12% of the variation in low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TGs)[3]
To search the human genome for lowfrequency and rare variants associated with TG levels, we first tested associations with 13,074,236 single-nucleotide variants (SNV) and 1,122,542 biallelic indels (MAF Z0.1%) called from whole-genome-sequence data (Supplementary Table 2)

Summary

Introduction

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. (s.e. 1⁄4 0.27 per minor allele (P-value 1⁄4 8.0 Â 10 À 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 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. Analyses revealed replicable evidence of a rare, functional, variant in the APOC3 gene (rs138326449-A, MAF B0.25% in the British population) strongly associated with plasma TG levels This represents one of the first examples of a rare, large effect variant identified from WGS at a population based scale

Methods

Results

Conclusion