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Nat Commun. 2014 Sep 16;5:4871. doi: 10.1038/ncomms5871.

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

Collaborators (192)

Al Turki S, Anderson C, Anney R, Antony D, Soler Artigas M, Ayub M, Balasubramaniam S, Barrett JC, Barroso I, Beales P, Bentham J, Bhattacharya S, Birney E, Blackwood D, Bobrow M, Bochukova E, Bolton P, Bounds R, Boustred C, Breen G, Calissano M, Carss K, Chatterjee K, Chen L, Ciampi A, Cirak S, Clapham P, Clement G, Coates G, Collier D, Cosgrove C, Cox T, Craddock N, Crooks L, Curran S, Curtis D, Daly A, Danecek P, Davey Smith G, Day-Williams A, Day IN, Down T, Du Y, Dunham I, Durbin R, Edkins S, Ellis P, Evans D, Faroogi S, Fatemifar G, Fitzpatrick DR, Flicek P, Flyod J, Foley AR, Franklin CS, Futema M, Gallagher L, Gaunt T, Geihs M, Geschwind D, Greenwood C, Griffin H, Grozeva D, Guo X, Guo X, Gurling H, Hart D, Hendricks A, Holmans P, Howie B, Huang J, Huang L, Hubbard T, Humphries SE, Hurles ME, Hysi P, Jackson DK, Jamshidi Y, Jing T, Joyce C, Kaye J, Keane T, Keogh J, Kemp J, Kennedy K, Kolb-Kokocinski A, Lachance G, Langford C, Lawson D, Lee I, Lek M, Liang J, Lin H, Li R, Li Y, Liu R, Lönnqvist J, Lopes M, Lotchkova V, MacArthur D, Marchini J, Maslen J, Massimo M, Mathieson I, Marenne G, McCarthy S, McGuffin P, McIntosh A, McKechanie AG, McQuillin A, Memari Y, Metrustry S, Min J, Mitchison H, Moayyeri A, Morris J, Muddyman D, Muntoni F, Northstone K, O'Donnovan M, Onoufriadis A, O'Rahilly S, Oualkacha K, Owen MJ, Palotie A, Panoutsopoulou K, Parker V, Parr JR, Paternoster L, Paunio T, Payne F, Perry J, Pietilainen O, Plagnol V, Quaye L, Quail MA, Raymond L, Rehnström K, Richards B, Ring S, Ritchie GR, Roberts N, Savage DB, Scambler P, Schiffels S, Schmidts M, Schoenmakers N, Semple RK, Serra E, Sharp SI, Shihab H, Shin SY, Skuse D, Small K, Soranzo N, Southam L, Spasic-Boskovic O, Spector T, St Clair D, Stalker J, Stevens E, St Pourcian B, Sun J, Surdulescu G, Suvisaari J, Tachmazidou I, Timpson N, Tobin MD, Valdes A, Van Kogelenberg M, Vijayarangakannan P, Visscher PM, Wain LV, Walter K, Walters JT, Wang G, Wang J, Wang Y, Ward K, Wheeler E, Whyte T, Williams H, Williamson KA, Wilson C, Wilson SG, Wong K, Xu C, Yang J, Zeggini E, Zhang F, Zhang P, Zheng HF.

Author information

1
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
2
Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
3
Department of Biomedical and Surgical Sciences, Ospedale Civile Maggiore, Azienda Ospedaliera-University of Verona, Verona, Italy.
4
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK [2] Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 0QQ, UK.
5
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
6
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
7
Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
8
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Box 285, Hills Road, Cambridge CB2 0SL, UK.
9
The Avon Longitudinal Study of Parents and Children, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
10
D2K Research Group, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
11
Horokopio University Athens, Eleftheriou Venizelou 70, Kallithea 176 76, Greece.
12
Division of Nephrology, Department of Internal Medicine and Medical Specialties, Catholic University, Largo Francesco Vito 1-00198, Rome, Italy.
13
1] Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK [2] Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2.

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.

PMID:
25225788
PMCID:
PMC4167609
DOI:
10.1038/ncomms5871
[Indexed for MEDLINE]
Free PMC Article

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