An immediate concern that arises in reviewing these definitions of EP, as pointed out previously by Walters and Owen,4 is that they do not discriminate between a ‘liability-index’ and a ‘mediational’ model for EPs.5 For the ‘liability-index’ model, Walters and Owen use the somewhat derogatory term ‘epiphenomenon.’ Those who prefer the term intermediate phenotype3 implicitly assume a mediational model but rarely state this explicitly. As seen in Figure 1a, an EP liability-index (or ‘risk indicator’) model specifies that a common set of genes increase risk both for a dichotomous PD and for a continuous EP. It is in essence a model of pleiotropy in which one set of genetic variants causes variation in both EP and disease risk. Figure 1b shows the mediational model for EP, which makes the stronger assumption that the causal pathway from genetic variations to PD passes exclusively through EP.
