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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Huang, Jie 
Howie, Bryan 
McCarthy, Shane 
Memari, Yasin 
Walter, Klaudia 

Abstract

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.

Description

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Gene Frequency, Genetic Variation, Genome, Human, Genotype, Haplotypes, Humans, Italy, Middle Aged, Models, Genetic, Models, Statistical, Polymorphism, Single Nucleotide, United Kingdom, White People, Young Adult

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

6

Publisher

Springer Science and Business Media LLC
Sponsorship
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0513-10109)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12012/5/B)
Wellcome Trust (095515/Z/11/Z)
Wellcome Trust (100574/Z/12/Z)
Wellcome Trust (098497/Z/12/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (098498/Z/12/Z)
Wellcome Trust (095564/Z/11/Z)
European Commission (257082)
Wellcome Trust (091551/Z/10/A)
Wellcome Trust (091310/Z/10/Z)
TCC (None)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)