Toward clarifying the genetic basis for psychiatric disorders, an endophenotype approach focuses on characterizing narrower mechanistic processes that are more proximally related to genetic variation and in turn confer risk for a given clinical condition (Gottesman & Gould, 2003; Gottesman & Shields, 1973). Endophenotypes are defined as genetically-influenced characteristics that putatively connect the dots from specific sources of genetic variation to increases or decreases in the probability of having a disorder, as illustrated in Figure 3. Genetic variation is theorized to directly result in transcriptional differences, which then result in systems-level differences, which, in turn, result in the observed endophenotypic variation, and thereby proximally influences risk for the disorder. More simply, endophenotypes are the intervening psychobiological mediators between specific forms of genetic variation and disorder liability. Thus, a key element for the endophenotype approach is the importance of refining the complex pathways by which risk is communicated from the genome to an individual’s clinical status. By being more closely associated with genetic variation, endophenotypes are theorized to be more reliable and reflect larger magnitude relationships, making them easier to detect
