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. Ring, Amadou 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 and Nicole Soranzo ()
Additional contact information
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
Marta Futema: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London
Lorraine Southam: Wellcome Trust Sanger Institute
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
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

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5871

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