A more challenging and somewhat more controversial approach has been to combine individual-level data from cases with several related or even unrelated conditions and compare them to a common control group,in an effort to expand sample size and increase study power for each condition. The success of this method was demonstrated by the landmark Wellcome Trust Case Control Consortium (WTCCC) study of 2000 cases of each of seven common diseases and 3000 shared controls (34). This study provided many fundamental methodologic advances, including demonstration of the robustness of a single control group, the value of using cases of some diseases as controls for others, the greater power provided by increased sample size (numbers of subjects) rather than increased genomic coverage (numbers of SNPs), the critical need for manual review of automated genotyping calls, and the reliability of imputed genotypes for SNPs that were not actually typed by the genotyping platform. This approach of common controls and combined case groups used as controls was also employed by the WTCCC in its smaller study of 14,500 nonsynonymous SNPs in four autoimmune diseases,
