A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans
Authors: Timpson Nicholas J. , Walter Klaudia , Min Josine L. , Tachmazidou Ioanna , Malerba Giovanni , Shin So-Youn , Chen Lu , Futema Marta , Southam Lorraine , Iotchkova Valentina , Cocca Massimiliano , Huang Jie , Memari Yasin , McCarthy Shane , Danecek Petr , Muddyman Dawn , Mangino Massimo , Menni Cristina , Perry John R. B. , Ring Susan M. , Gaye Amadou , Dedoussis George , Farmaki Aliki-Eleni , Burton Paul , Talmud Philippa J. , Gambaro Giovanni , Spector Tim D. , Smith George Davey , Durbin Richard , Richards J Brent , Humphries Steve E. , Zeggini Eleftheria , Soranzo Nicole ,   UK1OK consortium members, Al Turki Saeed , Anderson Carl , Anney Richard , Antony Dinu , Soler Artigas Maria , Ayub Muhammad , Balasubramaniam Senduran , Barrett Jeffrey C. , Barroso Inês , Beales Phil , Bentham Jamie , Bhattacharya Shoumo , Birney Ewan , Blackwood Douglas , Bobrow Martin , Bochukova Elena , Bolton Patrick , Bounds Rebecca , Boustred Chris , Breen Gerome , Calissano Mattia , Carss Keren , Chatterjee Krishna , Chen Lu , Ciampi Antonio , Cirak Sebhattin , Clapham Peter , Clement Gail , Coates Guy , Collier David , Cosgrove Catherine , Cox Tony , Craddock Nick , Crooks Lucy , Curran Sarah , Curtis David , Daly Allan , Danecek Petr , Davey Smith George , Day-Williams Aaron , Day Ian N. M. , Down Thomas , Du Yuanping , Dunham Ian , Durbin Richard , Edkins Sarah , Ellis Peter , Evans David , Faroogi Sadaf , Fatemifar Ghazaleh , Fitzpatrick David R. , Flicek Paul , Flyod James , Foley A Reghan , Franklin Christopher S , Futema Marta , Gallagher Louise , Gaunt Tom , Geihs Matthias , Geschwind Daniel , Greenwood Celia , Griffin Heather , Grozeva Detelina , Guo Xueqin , Guo Xiaosen , Gurling Hugh , Hart Deborah , Hendricks Audrey , Holmans Peter , Howie Bryan , Huang Jie , Huang Liren , Hubbard Tim , Humphries Steve E. , Hurles Matthew E. , Hysi Pirro , Jackson David K. , Jamshidi Yalda , Jing Tian , Joyce Chris , Kaye Jane , Keane Thomas , Keogh Julia , Kemp John , Kennedy Karen , Kolb-Kokocinski Anja , Lachance Genevieve , Langford Cordelia , Lawson Daniel , Lee Irene , Lek Monkol , Liang Jieqin , Lin Hong , Li Rui , Li Yingrui , Liu Ryan , Lönnqvist Jouko , Lopes Margarida , Lotchkova Valentina , MacArthur Daniel , Marchini Jonathan , Maslen John , Massimo Mangino , Mathieson Iain , Marenne Gaëlle , McCarthy Shane , McGuffin Peter , McIntosh Andrew , McKechanie Andrew G. , McQuillin Andrew , Memari Yasin , Metrustry Sarah , Min Josine , Mitchison Hannah , Moayyeri Alireza , Morris James , Muddyman Dawn , Muntoni Francesco , Northstone Kate , O'Donnovan Michael , Onoufriadis Alexandros , O'Rahilly Stephen , Oualkacha Karim , Owen Michael J. , Palotie Aarno , Panoutsopoulou Kalliope , Parker Victoria , Parr Jeremy R. , Paternoster Lavinia , Paunio Tiina , Payne Felicity , Perry John , Pietilainen Olli , Plagnol Vincent , Quaye Lydia , Quail Michael A. , Raymond Lucy , Rehnström Karola , Richards Brent , Ring Susan , Ritchie Graham R. S. , Roberts Nicola , Savage David B. , Scambler Peter , Schiffels Stephen , Schmidts Miriam , Schoenmakers Nadia , Semple Robert K. , Serra Eva , Sharp Sally I. , Shihab Hasheem , Shin So-Youn , Skuse David , Small Kerrin , Soranzo Nicole , Southam Lorraine , Spasic-Boskovic Olivera , Spector Tim , St Clair David , Stalker Jim , Stevens Elizabeth , St Pourcian Beate , Sun Jianping , Surdulescu Gabriela , Suvisaari Jaana , Tachmazidou Ionna , Timpson Nicholas , Tobin Martin D. , Valdes Ana , Van Kogelenberg Margriet , Vijayarangakannan Parthiban , Visscher Peter M. , Wain Louise V. , Walter Klaudia , Walters James T. R. , Wang Guangbiao , Wang Jun , Wang Yu , Ward Kirsten , Wheeler Elanor , Whyte Tamieka , Williams Hywel , Williamson Kathleen A. , Wilson Crispian , Wilson Scott G. , Wong Kim , Xu ChangJiang , Yang Jian , Zeggini Eleftheria , Zhang Fend , Zhang Pingbo , Zheng Hou-Feng 
Published: September 2014

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.