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)

45 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4871
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 2014

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  • Projects

    MRC UoB UNITE Unit - programme 3

    Timpson, N. J. & Timpson, N. J.

    1/06/1331/03/18

    Project: Research

    MRC UoB UNITE Unit - Programme 1

    Davey Smith, G.

    1/06/1331/03/18

    Project: Research

    EXTENSION OF RD1321 VIA IOP.

    Golding, J.

    1/02/011/02/06

    Project: Research

    Cite this

    Timpson, N. J., Walter, K., Min, J. L., Tachmazidou, I., Malerba, G., Shin, S-Y., 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, J. R. B., ... UK1OK consortium members (2014). A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans. Nature Communications, 5, 4871. https://doi.org/10.1038/ncomms5871