Gottesman and Gould defined endophenotypes as “measurable components unseen by the unaided eye along the pathways between disease and distal genotype”, and argued that endophenotypes should be “simpler clues to genetic underpinnings than the disease syndrome itself” [2], although it has been more recently recognized that there is likely a gradient of endophenotypes, some of which are closer to gene action and others that are closer to the phenotype [14]. They delineated five criteria: A candidate endophenotype should be (1) associated with illness; (2) heritable; (3) state-independent (present whether or not illness is active); (4) co-segregate with illness within families; and (5) found in a higher rate in the unaffected relatives of affected individuals than in the general population [3]. Others have agreed that endophenotypes should reflect causes rather than effects of disorders, and suggest that endophenotypes should be measured quantitatively [15, 16].
