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.

中文翻译：

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在全基因组病例对照研究中使用超常态，未筛选和家族史筛选的对照对遗传相关性估计的影响。

传统上，在疾病A的正常病例对照研究中，对照定义为未发生疾病的对照。但是，在全基因组关联（GWA）研究中，有时会（a）对对照进行筛查，或者对（b）针对疾病A和疾病B进行筛查，从而产生超正常对照。通过模拟，我们检查了使用未筛选的，正常的和超正常的对照对两种疾病（A和B）之间观察到的遗传相关性有何影响。正常对照产生遗传相关性的无偏估计。但是，未经筛选和超正常的对照都偏向遗传相关性。随着两种疾病人群患病率的升高，偏倚的强度也随之增加。对于超常态对照，当真正的遗传相关性较低时，偏倚的绝对值会更大。使用非屏蔽控件可以看到相反的结果。增加对对照一级亲属的筛查大大增加了与超正常对照的遗传相关性偏倚，但仅对对照进行相关疾病筛查时影响最小。