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Nature Research (part of Springer Nature), Nature Communications, (6), p. 8111

DOI: 10.1038/ncomms9111



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

Journal article published in 2015 by Elisabeth M. van Leeuwen, Em van Leeuwen, Cornelia M. van Duijn, Saeed Al Turki, Antoinette Amuzu, Carl A. Anderson, Maria Soler Artigas, Richard Anney, Jie Huang, Dinu Antony, María Soler Artigas, Muhammad Ayub, Senduran Bala, Saeed Al Turki, Jeffrey C. Barrett and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.