Endophenotypes for psychiatric disorders: ready for primetime?

It is increasingly accepted that the imprecision of categorical psychiatric diagnoses can be a limiting factor in understanding the genetic basis of human behavioral abnormalities. Genetic investigation of endophenotypes--more precisely defined quantitative traits hypothesized to underlie disease syndromes--offers great promise as an alternative or complement to studies of categorical disease phenotypes. However, there is not yet standardization of the methods by which candidate endophenotypes should be chosen and applied. Fruitful endophenotype studies depend on the selection of heritable, quantitative traits that can be objectively and reliably measured. In this article, we propose guidelines for such investigations for psychiatric disorders, using endophenotypes previously proposed for bipolar disorder as particular examples. Gene expression studies and non-human primate models are recent developments in which an endophenotype approach might prove particularly valuable.