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

Abstract

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.

Keywords

Affiliated Institutions

• Institute of Genetics and Cancer GB
• Harokopio University of Athens GR
• Great Ormond Street Hospital GB
• Copenhagen University Hospital DK
• London School of Hygiene & Tropical Medicine GB
• University of California, Los Angeles US
• University of Cambridge GB
• St James's University Hospital GB
• King's College London GB
• St George's, University of London GB
• University College London GB
• St. James's Hospital IE
• Royal Edinburgh Hospital GB
• BGI Group (China) CN
• Wellcome Trust GB
• Wellcome/MRC Institute of Metabolic Science GB
• University of Oxford GB
• University of Verona IT
• University of London GB
• Broad Institute US
• IRCCS Materno Infantile Burlo Garofolo IT
• University of Copenhagen DK
• Erasmus MC NL
• Addenbrooke's Hospital GB
• Erasmus University Rotterdam NL
• Western General Hospital GB
• University of Bristol GB
• University of Edinburgh GB
• St Mary's Hospital GB
• Massachusetts General Hospital US
• Translational Research Institute AU
• European Bioinformatics Institute GB
• University of Leicester GB
• The University of Queensland AU
• Jewish General Hospital CA
• Centre for Human Genetics GB
• Gentofte Hospital DK
• Imperial College London GB
• McGill University CA
• Wellcome Sanger Institute GB
• University of Trieste IT
• Queen's University CA
• Great Ormond Street Hospital for Children NHS Foundation Trust GB
• Cardiff University GB
• Adaptive Biotechnologies (United States) US

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