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

2014; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/ncomms5871

2041-1723

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 R. Burton, Philippa J. Talmud, Giovanni Gambaro, Tim D. Spector, George Davey Smith, Richard Durbin, J. Brent Richards, Steve E. Humphries, Eleftheria Zeggini, Nicole Soranzo, Saeed Al Turki, Carl A. Anderson, Richard Anney, Dinu Antony, María Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Jeffrey C. Barrett, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena G. Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Petr Danecek, George Davey Smith, Aaron G. Day‐Williams, Ian N.M. Day, Thomas A. Down, Yuanping Du, Ian Dunham, Richard Durbin, Sarah Edkins, Peter Ellis, David M. Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Tom R. Gaunt, Matthias Geihs, Daniel Geschwind, Celia M.T. Greenwood, Heather Griffin, Detelina Grozeva, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey E. Hendricks, Peter Holmans, Bryan Howie, Jie Huang, Jie Huang, Tim Hubbard, Steve E. Humphries, Matthew E. Hurles, Pirro G. Hysi, David K. Jackson, Yalda Jamshidi, Jing Tian, Christopher Joyce, Jane Kaye, Thomas Keane, Julia M. Keogh, John P. Kemp, Karen Kennedy, Anja Kolb‐Kokocinski, Geneviève Lachance, Cordelia Langford, Daniel J. Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Rui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Lotchkova, Daniel G. MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Shane McCarthy, Peter McGuffin, Andrew M. McIntosh, Andrew G. McKechanie, Andrew McQuillin, Yasin Memari, Sarah Metrustry, Josine L. Min, Hannah M. Mitchison, Alireza Moayyeri, James Morris, Dawn Muddyman, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O’Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, John R. B. Perry, Olli Pietiläinen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Lucy Raymond, Karola Rehnström, J. Brent Richards, Susan M. Ring, Graham R. S. Ritchie, Nicola D. Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, Hasheem Shihab, So–Youn Shin, David Skuse, Kerrin S. Small, Nicole Soranzo, Lorraine Southam, Olivera Spasić-Bošković, Tim D. Spector, David St Clair, Jim Stalker, Elizabeth R. Stevens, Beate St Pourcian, Jianping Sun, Gabriela Surdulescu, Jaana Suvisaari, Ionna Tachmazidou, Nicholas J. Timpson, Martin D. Tobin, Ana M. Valdes, Margriet van Kogelenberg, Parthiban Vijayarangakannan, Peter M. Visscher, Louise V. Wain, Klaudia Walter, James Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Eleanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Scott G. Wilson, Kim Wong, Changjiang Xu, Jian Yang, Eleftheria Zeggini, F. Zhang, Pingbo Zhang, Hou-Feng Zheng,

Peroxisome Proliferator-Activated Receptors

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.