Imputation of low-coverage sequencing data from 150,119 UK Biobank genomes

Abstract

Recent work highlights the advantages of low-coverage whole genome sequencing (lcWGS), followed by genotype imputation, as a cost-effective genotyping technology for statistical and population genetics. The release of whole genome sequencing data for 150,119 UK Biobank (UKB) samples represents an unprecedented opportunity to impute lcWGS with high accuracy. However, despite recent progress1,2, current methods struggle to cope with the growing numbers of samples and markers in modern reference panels, resulting in unsustainable computational costs. For instance, the imputation cost for a single genome is 1.11{pound} using GLIMPSE v1.1.1 (GLIMPSE1) on the UKB research analysis platform (RAP) and rises to 242.8{pound} using QUILT v1.0.4. To overcome this computational burden, we introduce GLIMPSE v2.0.0 (GLIMPSE2), a major improvement of GLIMPSE, that scales sublinearly in both the number of samples and markers. GLIMPSE2 imputes a low-coverage genome from the UKB reference panel for only 0.08{pound} in compute cost while retaining high accuracy for both ancient and modern genomes, particularly at rare variants (MAF < 0.1%) and for very low-coverage samples (0.1x-0.5x).