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

Giovanni Gambaro, Nicholas J. Timpson, Klaudia Walter, Josine L. Min, Ioanna Tachmazidou, Giovanni Malerba, So-Youn Shin, Lu Chen, Marta Futema, Lorraine Southam, Valentina Iotchkova, Massimiliano Cocca, Jie Huang, Yasin Memari, Shane Mccarthy, Petr Danecek, Dawn Muddyman, Massimo Mangino, Cristina Menni, John R.B. PerrySusan M. Ring, Amadou Gaye, George Dedoussis, Aliki-Eleni Farmaki, Paul Burton, Philippa J. Talmud, Tim D. Spector, George Davey Smith, Richard Durbin, J Brent Richards, Steve E. Humphries, Eleftheria Zeggini, Nicole Soranzo, Saeed Al Turki, Carl Anderson, Senduran Balasubramaniam, Jeffrey C. Barrett, Iněs Barroso, Keren Carss, Peter Clapham, Guy Coates, Tony Cox, Lucy Crooks, Allan Daly, Aaron Day-Williams, Thomas Down, Sarah Edkins, Peter Ellis, Paul Flicek, James Flyod, Christopher S. Franklin, Matthias Geihs, Audrey Hendricks, Tim Hubbard, Matthew E. Hurles, David K. Jackson, Chris Joyce, Thomas Keane, Karen Kennedy, Anja Kolb-Kokocinski, Cordelia Langford, Margarida Lopes

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)4871-4871
Number of pages1
JournalNature Communications
Publication statusPublished - 2014


  • cholesterol


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