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Title: A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans
Authors: 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.
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.
Tachmazidou, I.
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.
First Published: 16-Sep-2014
Publisher: Nature Publishing Group
Citation: Nature Communications, 2014, 5:4871
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.
DOI Link: 10.1038/ncomms5871
eISSN: 2041-1723
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
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