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

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

Research output: Contribution to journalArticle

47 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 languageEnglish
Pages (from-to)10pp
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 2014

Fingerprint Dive into the research topics of 'A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans'. Together they form a unique fingerprint.

Cite this