The challenges in interpreting genetic correlation are similar to the challenges in MR. We highlight two difficulties. First, genetic correlation is immune to environmental confounding, but is subject to genetic confounding, analogous to confounding by pleiotropy in MR. For example, the genetic correlation between HDL and CAD in Figure 2 could result from a causal effect HDL→CAD, but could also be mediated by triglycerides (TG) [9, 56], represented graphically [57] as HDL←G→TG→CAD, where G is the set of genetic variants with effects on both HDL and TG. Extending genetic correlation to multiple genetically correlated phenotypes is an important direction for future work [58]. Second, although genetic correlation estimates are not biased by oversampling of cases, they are affected by other forms of biased sampling, such as misclassification [14] and case/control/covariate sampling (e.g., a BMI-matched study of T2D).
