A more extreme but convenient and cost-efficient design alternative, notably taken recently by the WTCCC [20], is the use of external controls that are collected independently with little reference to the population from which cases are selected. The large number of disease-unrelated SNPs measured in a GWAS can be utilized to evaluate and when applicable, correct for the confounding effect induced by the genetic ancestral disparity between the case and control groups. Therefore, the stringent requirement of control selection imposed according to the classical epidemiology paradigm could be relaxed to some extent. This view is supported by our analyses of two reconstructed studies with independently collected controls. It appears that an appropriate PC adjustment can effectively correct for the elevated confounding effect introduced by the use of less desirable controls.
