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

By Jie Huang, Bryan N. Howie, Shane A. McCarthy, Y. Memari, Klaudia Walter, J. Min, Petr Danecek, G. Malerba, E. Trabetti, Houfeng Zheng and 229 more. 2015

384 citations recorded by the source corpus.

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. Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Subfields: Genetics

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Citations in the corpus

Large-scale whole-genome sequencing of three diverse Asian populations in Singapore (2018, neutral): “We note that although it has become a common practice to merge multiple reference panels for better imputation, researchers need to be cautious with using the combined panels.(20,47) In our case, though the combined panel consisted of worldwide populations from 1KG3, it was not suitable for imputing”
A one penny imputed genome from next generation reference panels (2018, background): “5k – 10M) and target sample sizes (10-1000) considered.”