The imputation reference haplotype panel (e.g., 1000 Genomes or, in this case, our sequences) is a critical component of imputation. This is especially true for imputation of less common variants, which is highly sensitive to the degree of ancestry matching between the genotyped sample (to be imputed in) and the reference haplotype panel (e.g., 1000 Genomes), as well as the number of individuals in the reference haplotype panel. The number of individuals in the panel is important because imputation accuracy is in part a function of how many copies of a variant exist in the haplotype panel. If only one copy exists (i.e., a singleton), that variant will likely be difficult to impute accurately. One simple way to increase the number of copies of a variant is to increase the number of individuals in the haplotype panel. Since the number of individuals of European ancestry sequenced in the MTFS was over three times larger than the number of individuals of European ancestry in 1000 Genomes, we expected the use of our MTFS haplotype reference panel to provide significantly greater imputation accuracy over 1000 Genomes.
