factors emerge, one may begin to craft PRS as genetic instruments, that may be used to test the plausibility of causality among phenotypes, as long as the potential of pleiotropic effects remains tractable (from a biological and statistical perspective). Several tools have been developed to facilitate MR analyses [e.g., MR-Base: (Hemani et al., 2016) and for gene expression: Summary-data-based Mendelian Randomization (SMR): (Zhu et al., 2016)]. However, it is unclear whether the assumptions of MR analyses (e.g., lack of assortative mating; no confounding pathways) can truly be overcome, and may become more concerning for PRS analyses in light of extensive shared polygenic pathways (Cross-Disorder Group of the Psychiatric Genomics, 2013) and even potential omnigenic undergirding (Boyle et al., 2017).
