The first assumption is that intermediate phenotypes are more tractable to genetic mapping than a primary phenotype, principally because they are presumed to be closer to the underlying biology. That is, we assume that genetic associations for intermediate phenotypes will be less influenced by measurement error, environmental influences, or multiple pathway effects that are likely to complicate the analysis of primary phenotypes. If this is true, and in some cases it is where we are fortunate to have a well-placed intermediate measure, then smaller sample sizes might be sufficient to identify these intermediate phenotypes. This, in turn, also implies that the genetic architecture of intermediate phenotypes will be different to that of disease phenotypes. However one must contend with the important notions that (i) these intermediate phenotypes are often not available and (ii) with biological proximity often comes a lack of clinical or real life translation (especially in the field of psychological traits).
