Genotype imputation performance of three reference panels using African ancestry individuals

Abstract

Genotype imputation estimates unobserved genotypes from genome-wide makers, to increase genome coverage and power for genome-wide association studies. Imputation has been successful for European ancestry populations in which very large reference panels are available. Smaller subsets of African descent populations are available in 1000 Genomes (1000G), the Consortium on Asthma among African ancestry Populations in the Americas (CAAPA) and the Haplotype Reference Consortium (HRC). We compared the performance of these reference panels when imputing variation in 3747 African Americans (AA) from two cohorts (HCV and COPDGene) genotyped using Illumina Omni microarrays. The haplotypes of 2504 (1000G), 883 (CAAPA) and 32,470 individuals (HRC) were used as reference. We compared the number of variants, imputation quality, imputation accuracy and coverage between panels. In both cohorts, 1000G imputed 1.5-1.6× more variants than CAAPA and 1.2× more than HRC. Similar findings were observed for variants with imputation R² > 0.5 and for rare, low-frequency, and common variants. When merging imputed variants of the three panels, the total number was 62-63 M with 20 M overlapping variants imputed by all three panels, and a range of 5-15 M variants imputed exclusively with one of them. For overlapping variants, imputation quality was highest for HRC, followed by 1000G, then CAAPA, and improved as the minor allele frequency increased. 1000G, HRC and CAAPA provided high performance and accuracy for imputation of African American individuals, increasing the number of variants available for subsequent analyses. These panels are complementary and would benefit from the development of an integrated African reference panel.

Figure 1.

Relationship between imputation quality and minor allele frequency for all variants imputed with 1000G, CAAPA and HRC in the HCV cohort. The graph represents the mean of imputation R² in each minor allele frequency (MAF) bin (intervals of 0.001 for variants with MAF < 1% and intervals of 0.01 for for variants with MAF > 1%).

Figure 2.

Number of overlapping and unique variants imputed with 1000G, CAAPA and HRC for the HCV cohort. The intersection shows the number of variants (in millions) imputed with the three reference panels and the non-overlapping sections of the circles show the variants unique to each panel.

Figure 3.

Number of variants by imputation quality (R²) for all overlapping variants imputed with CAAPA, 1000G and HRC for the HCV cohort. The values on the gray line at imputation R²=0.5 correspond to the number of overlapping variants imputed with R²>= 0.5 with each panel.