title: A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans.
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.
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Walter
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tachmazidou
authors.affiliation: Department of Biomedical and Surgical Sciences, Ospedale Civile Maggiore, Azienda Ospedaliera-University of Verona, Verona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.affiliation: 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.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.affiliation: 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.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iotchkova
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cocca
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Petr
authors.initials: P
authors.lastname: Danecek
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Dawn
authors.initials: D
authors.lastname: Muddyman
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Box 285, Hills Road, Cambridge CB2 0SL, UK.
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.affiliation: The Avon Longitudinal Study of Parents and Children, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: D2K Research Group, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Amadou
authors.initials: A
authors.lastname: Gaye
authors.affiliation: Horokopio University Athens, Eleftheriou Venizelou 70, Kallithea 176 76, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dedoussis
authors.affiliation: Horokopio University Athens, Eleftheriou Venizelou 70, Kallithea 176 76, Greece.
authors.forename: Aliki-Eleni
authors.initials: AE
authors.lastname: Farmaki
authors.affiliation: D2K Research Group, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Burton
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.affiliation: Division of Nephrology, Department of Internal Medicine and Medical Specialties, Catholic University, Largo Francesco Vito 1-00198, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: 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.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: 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.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D053305:Apolipoprotein C-III / Q000235:genetics*; D002648:Child; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014280:Triglycerides / Q000097:blood*; D014427:Twins / Q000235:genetics; D044465:White People
chemical_list: D053305:Apolipoprotein C-III; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides