One immediate obstacle to this application of intermediate phenotypes is that we do not know which physiology is relevant to psychiatric disease. Kendler and Neale point out that it is “difficult in humans to actually discriminate between liability-index and mediational models, especially when joint models …. are plausible alternatives” [13]. If the phenotype is a consequence of disease, or a liability-index, it will not help with attempts to understand the biological basis of psychiatric illness through genetic analysis. A key step in the use of intermediate phenotypes is obtaining evidence that the phenotype lies on the causal pathway from gene to disease. As Kendler and Neale emphasize, establishing that aetiological relationship is not easy. Indeed, we could say that a major aim of intermediate phenotype research is to establish causal pathways, rather than starting from the premise that they are on the causal pathway.
