Recently, tag-SNP analyses have been augmented by a genotype-imputation approach, in which data analysis is not restricted to SNPs that have actually been genotyped. In imputation-based GWA studies7,8,67, densely genotyped reference individuals, typically from the HapMap Project, provide information for predicting the genotypes at SNP positions measured in the reference data but not in the study sample. These predicted genotypes are then tested for disease association. Imputation is possible because two haplotypes that are identical for a set of nearby markers are likely to share the intervening chromosomal stretch identically by descent. Thus, if one of the two haplotypes is genotyped more densely than the other, then genotypes at unmeasured positions in the more sparsely genotyped haplotype can be predicted by copying the genotypes from the more densely genotyped haplotype. Genome-wide imputation of study haplotypes proceeds by locally copying the most appropriate reference haplotypes in a probabilistic manner.
