Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel.pdf (486.06 kB)
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Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel.

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posted on 25.01.2018, 09:20 by Jie Huang, Bryan Howie, Shane McCarthy, Yasin Memari, Klaudia Walter, Josine L. Min, Petr Danecek, Giovanni Malerba, Elisabetta Trabetti, Hou-Feng Zheng, UK10K Consortium, Giovanni Gambaro, J. Brent Richards, Richard Durbin, Nicholas J. Timpson, Jonathan Marchini, Nicole Soranzo
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.


This study makes use of data generated by the UK10K Consortium. The Wellcome Trust provided funding for UK10K (award WT091310). N.S. is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the European Commission (EUFP7 EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510) and the NIHR. J.B.R. is funded by the CIHR, CQDM, FRSQ and the Jewish General Hospital. H.-F.Z. is supported by Canadian Institutes of Health Research. J.M. acknowledges support from the ERC (Grant no. 617306). NJT works in a unit supported by the UK Medical Research Council (MRC) (MC_UU_12013/3). For ALSPAC, we are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. For further details concerning the generation of UK10K sequence data, please see extended methods in reference 6. Key contributing studies from the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium appear in the lipids meta-analysis group, but we also acknowledge the support and contribution of the resource more generally. A full description of the collection and its component studies can be found here: DOI: 10.1371/journal.pone.0071345.



Nature Communications, 2015, 6, 8111

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Accession Codes: UK10K reference haplotypes are available from the European Genome-phenome archive under the accession codes EGAS00001000713 (EGA study) and EGAD00001000776 (EGA dataset) under managed access conditions ( Supplementary Information accompanies this paper at