The impact on estimations of genetic correlations by the use of super-normal, unscreened, and family-history screened controls in genome wide case-control studies

Traditionally, in normal case-control studies of disorder A, the controls are defined as those not developing the disorder. However, in genome wide association (GWA) studies, controls are sometimes (a) unscreened or (b) screened for both 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 absolute 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 controls are screened only for the relevant disease.