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

Author

Listed:
  • Nicholas J. Timpson

    (MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol)

  • Klaudia Walter

    (Wellcome Trust Sanger Institute)

  • Josine L. Min

    (MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol)

  • Ioanna Tachmazidou

    (Wellcome Trust Sanger Institute)

  • Giovanni Malerba

    (Ospedale Civile Maggiore, Azienda Ospedaliera-University of Verona)

  • So-Youn Shin

    (MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol)

  • Lu Chen

    (Wellcome Trust Sanger Institute
    University of Cambridge)

  • Marta Futema

    (Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London)

  • Lorraine Southam

    (Wellcome Trust Sanger Institute
    Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Valentina Iotchkova

    (Wellcome Trust Sanger Institute)

  • Massimiliano Cocca

    (Wellcome Trust Sanger Institute)

  • Jie Huang

    (Wellcome Trust Sanger Institute)

  • Yasin Memari

    (Wellcome Trust Sanger Institute)

  • Shane McCarthy

    (Wellcome Trust Sanger Institute)

  • Petr Danecek

    (Wellcome Trust Sanger Institute)

  • Dawn Muddyman

    (Wellcome Trust Sanger Institute)

  • Massimo Mangino

    (Kings College London)

  • Cristina Menni

    (Kings College London)

  • John R. B. Perry

    (MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital)

  • Susan M. Ring

    (The Avon Longitudinal Study of Parents and Children, School of Social and Community Medicine, University of Bristol)

  • Amadou Gaye

    (D2K Research Group, School of Social and Community Medicine, University of Bristol)

  • George Dedoussis

    (Horokopio University Athens, Eleftheriou Venizelou 70, Kallithea 176 76)

  • Aliki-Eleni Farmaki

    (Horokopio University Athens, Eleftheriou Venizelou 70, Kallithea 176 76)

  • Paul Burton

    (D2K Research Group, School of Social and Community Medicine, University of Bristol)

  • Philippa J. Talmud

    (Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London)

  • Giovanni Gambaro

    (Catholic University, Largo Francesco Vito 1-00198)

  • Tim D. Spector

    (Kings College London)

  • George Davey Smith

    (MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol)

  • Richard Durbin

    (Wellcome Trust Sanger Institute)

  • J Brent Richards

    (Kings College London
    Human Genetics, Epidemiology and Biostatistics, Jewish General Hospital, 3755 Cote-Ste-Catherine Road)

  • Steve E. Humphries

    (Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London)

  • Eleftheria Zeggini

    (Wellcome Trust Sanger Institute)

  • Nicole Soranzo

    (Wellcome Trust Sanger Institute
    University of Cambridge)

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.

Suggested Citation

  • 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, 2014. "A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5871
    DOI: 10.1038/ncomms5871
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