The Impact on Estimations of Genetic Correlations of the Use, in Genome Wide Case-Control Studies, of Super-Normal, Unscreened and Family-History Screened Controls

Traditionally, in normal case-control studies of disorder A, individuals with disorder A are screened-out of controls. However, in genome wide association (GWA) studies, controls are sometimes unscreened or screened for disorder A and disorder B, producing super-normal controls. Using simulations, we examine how the observed genetic correlations between two disorders (A and B) are influenced by the use of unscreened, normal, and super-normal controls. Normal controls produce unbiased estimates of the genetic correlation. However, unscreened and super-normal controls both bias upward the genetic correlations. The strength of the bias increases with increasing population prevalences for the two disorders. With super-normal controls, the magnitude of bias is stronger when the true genetic correlation is low. The opposite is seen with the use of unscreened controls. Adding screening of first-degree relatives of controls substantially increases the bias in genetic correlations with super-normal controls but has minimal impact when normal controls are used.