Our first experience with genotype imputation in the context of a genetic association study occurred when fine-mapping the Complement Factor H susceptibility locus for age-related macular degeneration (58). The locus shows evidence for multiple disease associated alleles and haplotypes (58, 63). Since multi-marker association analyses are much more convenient in the absence of missing genotype data (5), we used the software PHASE (97, 98) and early version of our MACH software (59) to fill in missing genotypes in our sample. In the absence of missing data, it is much easier to compare the evidence for association at different markers and to interpret the results of conditional association analyses that sought to identify independently associated markers. To validate our imputation approach, we masked 5% of the genotypes at the locus and showed that these could be imputed correctly >99% of the time by comparing each individual with a missing genotype to other individuals who shared a common haplotype or haplotypes.
