If the promise of endophenotype research for gene finding is to be realized, the endophenotype must simplify the task in a way that a clinical phenotype cannot. Because endophenotypes are derived from laboratory measures that often require expensive equipment, time consuming procedures, and/or specialized technical expertise, obtaining the types of large samples now common to molecular genetic research of complex traits is difficult and expensive. Although neither the endophenotype nor its genetic basis needs to be simpler than the associated clinical phenotype, the task of identifying genetic variants has to be easier in some way for endophenotypes to be useful. For example, genetic variants associated with the endophenotype should have larger effect sizes than those associated with the corresponding clinical phenotype, making it possible to detect them using a relatively small sample. As desirable as this is, there is at present no compelling evidence that an endophenotype can achieve this objective. Nevertheless, we have retained this utility criterion because if an endophenotype is shown to have this property, it would be of utmost significance to the value of collecting expensive, labor intensive endophenotype data and to providing etiologically relevant insights into likely underlying mechanisms.
