The first use of intermediate phenotypes is to aid gene discovery. For example, if a genetic study of major depression fails to identify a signal, then researchers may decide to focus their attention on cognitive variables instead, reasoning that individual differences in the processing of stimuli representing negative affect (such as a bias in the interpretation of sad or happy faces [14]) might be an important mechanistic pathway, better reflecting the underlying biology, and therefore more genetically tractable. In addition, they might include data indicating activity in brain areas involved in processing affective or motivational stimuli (such as the amygdala and nucleus accumbens). With results in hand, researchers can combine the additional phenotypes with the diagnostic information, searching for a subgroup in their data in which the genetic signal is enhanced. Alternatively (or additionally) they can work solely with the new phenotypes, hoping that, by solving the genetics of disease mechanism they can then later solve the genetics of disease itself (for example, a locus identified for the cognitive measures could be tested for association in the depression cohort). Of course, this approach depends on selecting the true disease model (i.e., the correct intermediate phenotypes).
