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

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.; Ring, S. M.; Gaye, A.; Dedoussis, G.; Farmaki, A.-E.; Burton, P.; Talmud, P. J.; Gambaro, G.; Spector, T. D.; Smith, G. D.; Durbin, R.; Richards, J. B.; Humphries, S. E.; Zeggini, E.; Soranzo, N.; Turki, S. A.; Anderson, C.; Anney, R.; Antony, D.; Artigas, Maria Soler; Ayub, M.; Balasubramaniam, S.; Barrett, J. C.; 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.; 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.; Day-Williams, A.; Day, I. N. M.; Down, T.; Du, Y.; Dunham, I.; Edkins, S.; Ellis, P.; Evans, D.; Faroogi, S.; Fatemifar, G.; Fitzpatrick, D. R.; Flicek, P.; Flyod, J.; Foley, A. R.; Franklin, C. S.; Gallagher, L.; Gaunt, T.; Geihs, M.; Geschwind, D.; Greenwood, C.; Griffin, H.; Grozeva, D.; Guo, X.; Gurling, H.; Hart, D.; Hendricks, A.; Holmans, P.; Howie, B.; Huang, L.; Hubbard, T.; Hurles, M. E.; Hysi, P.; Jackson, D. K.; 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.; McGuffin, P.; McIntosh, A.; McKechanie, A. G.; McQuillin, A.; Metrustry, S.; Mitchison, H.; Moayyeri, A.; Morris, J.; Muntoni, F.; Northstone, K.; O'Donnovan, M.; Onoufriadis, A.; O'Rahilly, S.; Oualkacha, K.; Owen, M. J.; Palotie, A.; Panoutsopoulou, K.; Parker, V.; Parr, J. R.; Paternoster, L.; Paunio, T.; Payne, F.; Pietilainen, O.; Plagnol, V.; Quaye, L.; Quail, M. A.; Raymond, L.; Rehnström, K.; Richards, B.; Ritchie, G. R. S.; Roberts, N.; Savage, D. B.; Scambler, P.; Schiffels, S.; Schmidts, M.; Schoenmakers, N.; Semple, R. K.; Serra, E.; Sharp, S. I.; Shihab, H.; Skuse, D.; Small, K.; Spasic-Boskovic, O.; Clair, D. S.; Stalker, J.; Stevens, E.; Pourcian, B. S.; Sun, J.; Surdulescu, G.; Suvisaari, J.; Tobin, M. D.; Valdes, A.; Van Kogelenberg, M.; Vijayarangakannan, P.; Visscher, P. M.; Wain, Louise V.; Walters, J. T. R.; Wang, G.; Wang, J.; Wang, Y.; Ward, K.; Wheeler, E.; Whyte, T.; Williams, H.; Williamson, K. A.; Wilson, C.; Wilson, S. G.; Wong, K.; Xu, C.; Yang, J.; Zhang, F.; Zhang, P.; Zheng, H.-F.

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

journal contribution

posted on 2016-02-19, 14:20 authored by N. J. Timpson, K. Walter, J. L. Min, I. Tachmazidou, G. Malerba, S.-Y. Shin, L. Chen, M. Futema, L. Southam, V. Iotchkova, M. Cocca, J. Huang, Y. Memari, S. McCarthy, P. Danecek, D. Muddyman, M. Mangino, C. Menni, J. R. B. Perry, S. M. Ring, A. Gaye, G. Dedoussis, A.-E. Farmaki, P. Burton, P. J. Talmud, G. Gambaro, T. D. Spector, G. D. Smith, R. Durbin, J. B. Richards, S. E. Humphries, E. Zeggini, N. Soranzo, S. A. Turki, C. Anderson, R. Anney, D. Antony, Maria Soler Artigas, M. Ayub, S. Balasubramaniam, J. C. Barrett, I. Barroso, P. Beales, J. Bentham, S. Bhattacharya, E. Birney, D. Blackwood, M. Bobrow, E. Bochukova, P. Bolton, R. Bounds, C. Boustred, G. Breen, M. Calissano, K. Carss, K. Chatterjee, A. Ciampi, S. Cirak, P. Clapham, G. Clement, G. Coates, D. Collier, C. Cosgrove, T. Cox, N. Craddock, L. Crooks, S. Curran, D. Curtis, A. Daly, A. Day-Williams, I. N. M. Day, T. Down, Y. Du, I. Dunham, S. Edkins, P. Ellis, D. Evans, S. Faroogi, G. Fatemifar, D. R. Fitzpatrick, P. Flicek, J. Flyod, A. R. Foley, C. S. Franklin, L. Gallagher, T. Gaunt, M. Geihs, D. Geschwind, C. Greenwood, H. Griffin, D. Grozeva, X. Guo, H. Gurling, D. Hart, A. Hendricks, P. Holmans, B. Howie, L. Huang, T. Hubbard, M. E. Hurles, P. Hysi, D. K. Jackson, Y. Jamshidi, T. Jing, C. Joyce, J. Kaye, T. Keane, J. Keogh, J. Kemp, K. Kennedy, A. Kolb-Kokocinski, G. Lachance, C. Langford, D. Lawson, I. Lee, M. Lek, J. Liang, H. Lin, R. Li, Y. Li, R. Liu, J. Lönnqvist, M. Lopes, V. Lotchkova, D. MacArthur, J. Marchini, J. Maslen, M. Massimo, I. Mathieson, G. Marenne, P. McGuffin, A. McIntosh, A. G. McKechanie, A. McQuillin, S. Metrustry, H. Mitchison, A. Moayyeri, J. Morris, F. Muntoni, K. Northstone, M. O'Donnovan, A. Onoufriadis, S. O'Rahilly, K. Oualkacha, M. J. Owen, A. Palotie, K. Panoutsopoulou, V. Parker, J. R. Parr, L. Paternoster, T. Paunio, F. Payne, O. Pietilainen, V. Plagnol, L. Quaye, M. A. Quail, L. Raymond, K. Rehnström, B. Richards, G. R. S. Ritchie, N. Roberts, D. B. Savage, P. Scambler, S. Schiffels, M. Schmidts, N. Schoenmakers, R. K. Semple, E. Serra, S. I. Sharp, H. Shihab, D. Skuse, K. Small, O. Spasic-Boskovic, D. S. Clair, J. Stalker, E. Stevens, B. S. Pourcian, J. Sun, G. Surdulescu, J. Suvisaari, M. D. Tobin, A. Valdes, M. Van Kogelenberg, P. Vijayarangakannan, P. M. Visscher, Louise V. Wain, J. T. R. Walters, G. Wang, J. Wang, Y. Wang, K. Ward, E. Wheeler, T. Whyte, H. Williams, K. A. Williamson, C. Wilson, S. G. Wilson, K. Wong, C. Xu, J. Yang, F. Zhang, P. Zhang, H.-F. Zheng

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.

Funding

This study makes use of data generated by the UK10K Consortium, derived from samples from the ALSPAC and TwinsUK data sets. A full list of the investigators who contributed to the generation of the data is available from www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. This work made use of data and samples generated by the 1958 Birth Cohort (NCDS). Access to these resources was enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council (grant numbers WT095219MA and G1001799). A full list of the financial, institutional and personal contributions to the development of the 1958 Birth Cohort Biomedical resource is available at www2.le.ac.uk/projects/birthcohort. Genotyping was undertaken as part of the Wellcome Trust Case-Control Consortium (WTCCC) under Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk. We also are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provide core support for ALSPAC. TwinsUK was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust and King’s College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. S.S. is supported by an Oak Foundation Research Fellowship. N.S. is supported by the Wellcome Trust (Grant Codes WT0980

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Nature Communications, 2014, 5:4871

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/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Health Sciences

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Nature Publishing Group

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2041-1723

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2014-07-30

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2016-02-19

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https://doi.org/10.1038/ncomms5871

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http://www.nature.com/ncomms/2014/140916/ncomms5871/full/ncomms5871.html

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en

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

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