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

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 Perry, Susan M RingAmadou Gaye, George Dedoussis, Aliki-Eleni Farmaki, Paul Burton, Philippa J Talmud, Giovanni Gambaro, Tim D Spector, George Davey Smith, Richard Durbin, J Brent Richards, Steve E Humphries, Eleftheria Zeggini, Nicole Soranzo, UK1OK consortium members

Research output: Contribution to journalArticle (Academic Journal)peer-review

58 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
JournalNature Communications
Publication statusPublished - 16 Sept 2014


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