Future studies should also evaluate potential increases in statistical power for gene- and region- based tests using TOPMed imputed data. To demonstrate the potential gains, we have performed a targeted analysis of genes previously identified for their association with white blood cell count or hemoglobin/hematocrit levels in exome genotyping arrays or exome sequencing studies. We compared gene-based SKAT test results at these known loci using TOPMed freeze 5b based imputation to gene-based tests performed using 1000G and HRC reference panels. These results are presented in S18–S21 Tables and demonstrate that in both African ancestry and Hispanic/Latino populations more previously implicated genes from exome arrays or sequencing based studies were significant using TOPMed freeze 5b as an imputation reference panel versus 1000G phase 3 or HRC imputation. Further exploration of gene- and region-based tests is warranted in future studies, however. We expect the combination of high-quality imputation and higher depth sequencing datasets in larger cohorts of individuals will provide increased power for all rare variant association analyses in diverse populations in the near future.
