The presence of population stratification (PS)—allele frequency differences between cases and controls due to systematic ancestry differences—can lead to greater than nominal type I error rate [5]–[11]. Differences in the origin of populations of cases and controls can arise if the two groups are recruited independently or have different inclusion criteria. Differences in ancestry between cases and controls can also occur even if cases and controls are drawn from the same heterogeneous population, such as the European American population, when the disease risk varies across subpopulations due to differences in distribution of unmeasured risk factors [5]. Although the potential for an increase in false positives in well-designed association studies conducted in a stratified population is indisputable 6, 7, 12, the extent and impact of PS on case-control association studies in practice, particularly in GWAS, can now be thoroughly investigated as empirical evidence from recent association studies becomes available.
