Genotype imputation, despite being a standard practice in modern genetic association studies, remains challenging in populations of Hispanic/Latino or African ancestry, particularly for rare variants [1–6]. One obstacle lies in the lack of appropriate whole genome sequence reference panels for these admixed populations. For individuals of European descent, the relevant haplotypes available have increased by more than 500 times from 120 phased sequences in HapMap2 [7] to more than 64,000 phased sequences in Haplotype Reference Consortium (HRC) [8] reference. However, HRC is predominantly European (other than included 1000 Genomes Project Phase 3 (1000G) SNPs) and includes mostly low-coverage sequencing data (4-8x coverage). The state-of-the-art reference panels for African-ancestry (AA) and Hispanic/Latino cohorts, including the 1000 Genomes Project Phase 3 (1000G) [9] and the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) [10], are at least one order of magnitude smaller than HRC. This is especially problematic given the complex LD structure in admixed populations. The NHLBI Trans-Omics for Precision Medicine (TOPMed) Project has recently generated deep-coverage (mean depth 30x) whole genome sequencing (WGS) on more than 50,000 individuals
