Efficient phasing and imputation of low-coverage sequencing data using large reference panels

Low-coverage whole genome sequencing followed by imputation has been proposed as a cost-effective genotyping approach for disease and population genetics studies. However, its competitiveness against SNP arrays is undermined as current imputation methods are computationally expensive and unable to leverage large reference panels. Here, we describe a method, GLIMPSE, for phasing and imputation of low-coverage sequencing datasets from modern reference panels. We demonstrate its remarkable performance across different coverages and human populations. It achieves imputation of a full genome for less than $1, outperforming existing methods by orders of magnitude, with an increased accuracy of more than 20% at rare variants. We also show that 1x coverage enables effective association studies and is better suited than dense SNP arrays to access the impact of rare variations. Overall, this study demonstrates the promising potential of low-coverage imputation and suggests a paradigm shift in the design of future genomic studies.