Identified pleiotropic variants likely reflect some combination of three different types of pleiotropy (Paaby & Rockman, 2013). Vertical (i.e., mediated) pleiotropy refers to a causal cascade, where the variant affects trait A, and trait A causes trait B, thereby introducing an indirect association between the variant and trait B. In contrast, horizontal pleiotropy reflects a variant that directly affects traits A and B. Horizontal pleiotropy can occur when a single variant codes for multiple molecular functions, when a variant affects a single upstream process with broad downstream effects, or when phenotypes share certain characteristics. For psychiatric disorders, the latter two cases are more plausible given overlapping symptoms (i.e., shared characteristics) and risk factors (i.e., shared upstream process) across disorders. Methods for discriminating between horizontal and vertical pleiotropy have found evidence for both when applied to human complex traits more generally (Verbanck, Chen, Neale, & Do, 2018; Zhu et al., 2018). This likely also holds for psychiatric traits, but largely remains to be tested. However, others have noted as indication against vertical pleiotropy a paucity of evidence that early onset disorders are causal for later onset disorders (Schijven, Veldink, & Luykx, 2020).
