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; Nicole Soranzo; UK1OK consortium members

doi:10.1038/ncomms5871

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 journal › Article (Academic Journal) › peer-review

63 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 language	English
Pages (from-to)	4871
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5871
Publication status	Published - 16 Sept 2014

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MRC UoB UNITE Unit - programme 3
Timpson, N. J. (Principal Investigator) & Timpson, N. J. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 1
Davey Smith, G. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
EXTENSION OF RD1321 VIA IOP.
Golding, J. (Principal Investigator)
1/02/01 → 1/02/06
Project: Research

Professor Nicholas John Timpson
- N.J.Timpsonbristol.acuk
- Bristol Medical School (PHS) - Professor of Genetic Epidemiology
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
- Cancer
Person: Academic , Member

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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

@article{7b24838f0c6943439c9b135ab3a85f60,

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.",

author = "Timpson, {Nicholas J} and Klaudia Walter and Min, {Josine L} and Ioanna Tachmazidou and Giovanni Malerba and So-Youn Shin and Lu Chen and Marta Futema and Lorraine Southam and Valentina Iotchkova and Massimiliano Cocca and Jie Huang and Yasin Memari and Shane McCarthy and Petr Danecek and Dawn Muddyman and Massimo Mangino and Cristina Menni and Perry, {John R B} and Ring, {Susan M} and Amadou Gaye and George Dedoussis and Aliki-Eleni Farmaki and Paul Burton and Talmud, {Philippa J} and Giovanni Gambaro and Spector, {Tim D} and Smith, {George Davey} and Richard Durbin and Richards, {J Brent} and Humphries, {Steve E} and Eleftheria Zeggini and Nicole Soranzo and {UK1OK consortium members}",

year = "2014",

month = sep,

day = "16",

doi = "10.1038/ncomms5871",

language = "English",

volume = "5",

pages = "4871",

journal = "Nature Communications",

issn = "2041-1723",

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Timpson, NJ, Walter, K, Min, JL, 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, JRB, Ring, SM, Gaye, A, Dedoussis, G, Farmaki, A-E, Burton, P, Talmud, PJ, Gambaro, G, Spector, TD, Smith, GD, Durbin, R, Richards, JB, Humphries, SE, Zeggini, E, Soranzo, N & UK1OK consortium members 2014, 'A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans', Nature Communications, vol. 5, pp. 4871. https://doi.org/10.1038/ncomms5871

TY - JOUR

T1 - A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

AU - Timpson, Nicholas J

AU - Walter, Klaudia

AU - Min, Josine L

AU - Tachmazidou, Ioanna

AU - Malerba, Giovanni

AU - Shin, So-Youn

AU - Chen, Lu

AU - Futema, Marta

AU - Southam, Lorraine

AU - Iotchkova, Valentina

AU - Cocca, Massimiliano

AU - Huang, Jie

AU - Memari, Yasin

AU - McCarthy, Shane

AU - Danecek, Petr

AU - Muddyman, Dawn

AU - Mangino, Massimo

AU - Menni, Cristina

AU - Perry, John R B

AU - Ring, Susan M

AU - Gaye, Amadou

AU - Dedoussis, George

AU - Farmaki, Aliki-Eleni

AU - Burton, Paul

AU - Talmud, Philippa J

AU - Gambaro, Giovanni

AU - Spector, Tim D

AU - Smith, George Davey

AU - Durbin, Richard

AU - Richards, J Brent

AU - Humphries, Steve E

AU - Zeggini, Eleftheria

AU - Soranzo, Nicole

AU - UK1OK consortium members

PY - 2014/9/16

Y1 - 2014/9/16

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms5871

DO - 10.1038/ncomms5871

M3 - Article (Academic Journal)

C2 - 25225788

SN - 2041-1723

VL - 5

SP - 4871

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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MRC UoB UNITE Unit - programme 3

MRC UoB UNITE Unit - Programme 1

EXTENSION OF RD1321 VIA IOP.

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Professor Nicholas John Timpson

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