Population sequencing of large phenotyped cohorts will allow direct association tests for low frequency variants, with a resolution determined by the LD structure. An alternative that is less expensive, albeit less accurate, is to impute variants from a sequenced reference panel into previously genotyped samples28, 29. We evaluated the accuracy of imputation that used the current low coverage project haplotypes as the reference panel. Specifically, we compared genotypes derived by deep sequencing of one individual in each trio (the fathers) with genotypes derived using the HapMap 3 genotype data (which combined data from the Affymetrix 6.0 and Illumina 1M arrays) in those same two individuals and imputation based on the low coverage project haplotypes to fill in their missing genotypes. At variant sites (i.e., where the father was not homozygous for the reference), imputation accuracy was highest for SNPs at which the minor allele was observed at least 6 times in our low coverage samples, with an error rate of ~4% in CEU and ~10% in YRI, and became progressively worse for rarer SNPs, with error rates of 35% for sites where the minor allele was observed only twice in the low coverage samples (Fig. 4a).
