Fig. 1: Graphical representation illustrating the benefits of combining the results from different reference panels.

a Comparison of the number of variants after the imputation with four reference panels (info score ≥ 0.7), and combining them, colored according to MAF and variant type (SNP vs alternative forms of variation, such as indels). As shown in the bar plot, combining the results from the four reference panels increased the final set of variants for association testing when compared with the results for each of the panels alone (GoNL, UK10K, 1000G Phase 3, or HRC), especially in the low and rare frequency spectrum. For example, we covered up to 5.5 M rare variants (0.01> MAF > 0.001) by combining panels, while only 2.3 M, 2.9 M, 3.2 M, and 3.8 M of rare variants were imputed independently with GoNL, UK10K, 1000G phase 3, and HRC, respectively. b Comparison of the contribution of each reference panel in the combined results. Each bar represents the number of variants that had the best imputation accuracy for a given reference panel. As shown in the figure, although the HRC panel showed overall higher imputation scores, as it provided around 10 of the final 16 M variants, the contribution of the other reference panels, primarily with non-SNP variants, was substantial. Indels seen in the bar plot for HRC correspond to genotyped indels. All variants with info score <0.7, MAF < 0.001, and HWE for controls p < 1.0 × 10⁻⁶ were filtered. c Percentage of high-quality imputed variants (IMPUTE2-info score ≥ 0.7) with an allelic dosage R² ≥ 0.5 between sequenced genotypes in UK10K samples vs variants imputed in the same UK10K samples using 1000G phase 3, GoNL, and HRC reference panels for the autosomes. The percentage of high-quality imputed variants with allelic dosage R² values (y axis) are represented across several MAF ranges (x-axis) for each of the reference panels and the combined panels imputed results. The combination of the three reference panels outperforms the single reference panels with 97.74% of variants with R² ≥ 0.5. d Percentage of variants in the X chromosome with an IMPUTE2-info score ≥ 0.7 and with an allelic dosage R² ≥ 0.5 for UK10K imputed genotypes across MAF ranges for 1000G phase 3, GoNL, and HRC reference panels and the combined results. The combination of the results from the three panels outperforms single reference panels with 93.89% of variants with allelic dosage R² ≥ 0.5. e Venn Diagram illustrating the loci identified by each reference panel. New loci are depicted in bold. As shown in this figure, only 67 of the 94 GWAS significant loci were identified by all four reference panels, while 27 of them (28.7%) were only identified by one, two, or three of the four panels.