Figure 2.

Directed acyclic graph illustrating why pleiotropic bias is less likely in MR studies of protein expression than in studies using downstream phenotypic traits as risk factors. Here, $G$ denotes the genetic instrument, $P$ protein expression, $B$ the downstream biomarker, $Y$ the outcome and $U$ denotes confounding factors. Both types of MR studies are affected by pleiotropy due to “direct” effects of the genetic instrument on the outcome ($G\to Y$ pathway), but standard MR analyses are also subject to pleiotropy due to potential effects of the protein on the outcome ($G\to P\to Y$ pathway) which is not the case for studies of disease progression. MR, Mendelian randomization.