Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel
Authors: Huang Jie , Howie Bryan , McCarthy Shane , Memari Yasin , Walter Klaudia , Min Josine L. , Danecek Petr , Malerba Giovanni , Trabetti Elisabetta , Zheng Hou-Feng ,   UK10K Consortium, Al Turki Saeed , Amuzu Antoinette , Anderson Carl A. , Anney Richard , Antony Dinu , Artigas María Soler , Ayub Muhammad , Bala Senduran , Barrett Jeffrey C. , Barroso Inês , Beales Phil , Benn Marianne , Bentham Jamie , Bhattacharya Shoumo , Birney Ewan , Blackwood Douglas , Bobrow Martin , Bochukova Elena , Bolton Patrick F. , Bounds Rebecca , Boustred Chris , Breen Gerome , Calissano Mattia , Carss Keren , Pablo Casas Juan , Chambers John C. , Charlton Ruth , Chatterjee Krishna , Chen Lu , Ciampi Antonio , Cirak Sebahattin , Clapham Peter , Clement Gail , Coates Guy , Cocca Massimiliano , Collier David A. , Cosgrove Catherine , Cox Tony , Craddock Nick , Crooks Lucy , Curran Sarah , Curtis David , Daly Allan , Day Ian N. M. , Day-Williams Aaron , Dedoussis George , Down Thomas , Du Yuanping , van Duijn Cornelia M. , Dunham Ian , Edkins Sarah , Ekong Rosemary , Ellis Peter , Evans David M. , Farooqi I. Sadaf , Fitzpatrick David R. , Flicek Paul , Floyd James , Foley A. Reghan , Franklin Christopher S. , Futema Marta , Gallagher Louise , Gasparini Paolo , Gaunt Tom R. , Geihs Matthias , Geschwind Daniel , Greenwood Celia , Griffin Heather , Grozeva Detelina , Guo Xiaosen , Guo Xueqin , Gurling Hugh , Hart Deborah , Hendricks Audrey E. , Holmans Peter , Huang Liren , Hubbard Tim , Humphries Steve E. , Hurles Matthew E. , Hysi Pirro , Iotchkova Valentina , Isaacs Aaron , Jackson David K. , Jamshidi Yalda , Johnson Jon , Joyce Chris , Karczewski Konrad J. , Kaye Jane , Keane Thomas , Kemp John P. , Kennedy Karen , Kent Alastair , Keogh Julia , Khawaja Farrah , Kleber Marcus E. , van Kogelenberg Margriet , Kolb-Kokocinski Anja , Kooner Jaspal S. , Lachance Genevieve , Langenberg Claudia , Langford Cordelia , Lawson Daniel , Lee Irene , van Leeuwen Elisabeth M. , Lek Monkol , Li Rui , Li Yingrui , Liang Jieqin , Lin Hong , Liu Ryan , Lönnqvist Jouko , Lopes Luis R. , Lopes Margarida , Luan Jian'an , MacArthur Daniel G. , Mangino Massimo , Marenne Gaëlle , März Winfried , Maslen John , Matchan Angela , Mathieson Iain , McGuffin Peter , McIntosh Andrew M. , McKechanie Andrew G. , McQuillin Andrew , Metrustry Sarah , Migone Nicola , Mitchison Hannah M. , Moayyeri Alireza , Morris James , Morris Richard , Muddyman Dawn , Muntoni Francesco , Nordestgaard Børge G. , Northstone Kate , O'Donovan Michael C. , O'Rahilly Stephen , Onoufriadis Alexandros , Oualkacha Karim , Owen Michael J. , Palotie Aarno , Panoutsopoulou Kalliope , Parker Victoria , Parr Jeremy R. , Paternoster Lavinia , Paunio Tiina , Payne Felicity , Payne Stewart J. , Perry John R. B. , Pietilainen Olli , Plagnol Vincent , Pollitt Rebecca C. , Povey Sue , Quail Michael A. , Quaye Lydia , Raymond Lucy , Rehnström Karola , Ridout Cheryl K. , Ring Susan , Ritchie Graham R. S. , Roberts Nicola , Robinson Rachel L. , Savage David B. , Scambler Peter , Schiffels Stephan , Schmidts Miriam , Schoenmakers Nadia , Scott Richard H. , Scott Robert A. , Semple Robert K. , Serra Eva , Sharp Sally I. , Shaw Adam , Shihab Hashem A. , Shin So-Youn , Skuse David , Small Kerrin S. , Smee Carol , Smith George Davey , Southam Lorraine , Spasic-Boskovic Olivera , Spector Timothy D. , St Clair David , St Pourcain Beate , Stalker Jim , Stevens Elizabeth , Sun Jianping , Surdulescu Gabriela , Suvisaari Jaana , Syrris Petros , Tachmazidou Ioanna , Taylor Rohan , Tian Jing , Tobin Martin D. , Toniolo Daniela , Traglia Michela , Tybjaerg-Hansen Anne , Valdes Ana M. , Vandersteen Anthony M. , Varbo Anette , Vijayarangakannan Parthiban , Visscher Peter M. , Wain Louise V. , Walters James T. R. , Wang Guangbiao , Wang Jun , Wang Yu , Ward Kirsten , Wheeler Eleanor , Whincup Peter , Whyte Tamieka , Williams Hywel J. , Williamson Kathleen A. , Wilson Crispian , Wilson Scott G. , Wong Kim , Xu ChangJiang , Yang Jian , Zaza Gianluigi , Zeggini Eleftheria , Zhang Feng , Zhang Pingbo , Zhang Weihua , Gambaro Giovanni , Richards J. Brent , Durbin Richard , Timpson Nicholas J. , Marchini Jonathan , Soranzo Nicole 
Published: September 2015

AbstractImputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.