Our simulations clearly indicate that tests based on the accumulation of minor alleles at rare variants identified through re-sequencing are always more powerful than conventional tests applied to SNPs present on GWA chips, particularly in the presence of substantial allelic heterogeneity. We have assumed a discovery panel of 1,000 individuals from the same population from which the analysis cohort has been ascertained which may not always be the case. With the expense of re-sequencing efforts, focussed studies of samples from the analysis cohort are likely to be much smaller, and thus less powerful for rare variant discovery, although pooling may provide a more efficient initial screening step. Publicly available re-sequencing panels, such as those that will be released through the 1,000 Genomes project may not be matched for ancestry with the analysis cohort. These panels will miss rare variants specific to the population from which the analysis cohort has been ascertained, and may lead to genotyping of variants which are, in fact, monomorphic.
