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Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel.

Huang, J; Howie, B; McCarthy, S; Memari, Y; Walter, K; Min, JL; Danecek, P; Malerba, G; Trabetti, E; Zheng, H-F; et al. Huang, J; Howie, B; McCarthy, S; Memari, Y; Walter, K; Min, JL; Danecek, P; Malerba, G; Trabetti, E; Zheng, H-F; UK10K Consortium; Gambaro, G; Richards, JB; Durbin, R; Timpson, NJ; Marchini, J; Soranzo, N (2015) Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. Nat Commun, 6. p. 8111. ISSN 2041-1723
SGUL Authors: Jamshidi, Yalda

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Imputing 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.

Item Type: Article
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Keywords: Adolescent, Adult, Aged, Aged, 80 and over, Alleles, European Continental Ancestry Group, Gene Frequency, Genetic Variation, Genome, Human, Genotype, Haplotypes, Humans, Italy, Middle Aged, Models, Genetic, Models, Statistical, Polymorphism, Single Nucleotide, United Kingdom, Young Adult, UK10K Consortium, Humans, Models, Statistical, Gene Frequency, Genotype, Haplotypes, Polymorphism, Single Nucleotide, Alleles, Genome, Human, Models, Genetic, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, European Continental Ancestry Group, Italy, Genetic Variation, Young Adult, United Kingdom, MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Nat Commun
ISSN: 2041-1723
Language: eng
14 September 2015Published
17 July 2015Accepted
Publisher License: Creative Commons: Attribution 4.0
Project IDFunderFunder ID
PG/13/66/30442British Heart Foundation
095564Wellcome Trust
UNSPECIFIEDDepartment of Health
102215Wellcome Trust
096599Wellcome Trust
RG/10/17/28553British Heart Foundation
MC_UU_12013/1Medical Research Council
095515Wellcome Trust
RG/10/13/28570British Heart Foundation
WT098051Wellcome Trust
MC_UU_12015/1Medical Research Council
WT091310Wellcome Trust
098498Wellcome Trust
MC_PC_15018Medical Research Council
098497Wellcome Trust
100574Wellcome Trust
MC_UU_12013/3Medical Research Council
MR/L010305/1Medical Research Council
100140Wellcome Trust
G0800509Medical Research Council
091551Wellcome Trust
257082European Commission
HEALTH-F5-2011-282510European Commission
617306European Research Council
PubMed ID: 26368830
Web of Science ID: WOS:000362948800002
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