Of critical significance are investigations that establish the endophenotype as a measure of disorder risk. Those with the disorder should continue to display the endophenotype even when the disorder remits, and those who possess the endophenotype are by definition at elevated risk for subsequently developing the disorder. The ideal endophenotype would be present during fetal development and immutable thereafter. However, given the complexity of brain development and the many phenotypic changes associated with growth and maturation during childhood, few if any of the commonly considered endophenotypes for adult psychiatric disorder are likely to be detectable in the same form early in life or throughout the lifespan. Indeed, how a characteristic changes with development may itself constitute an endophenotype; e.g., an endophenotype could index the rate of maturation of a brain system (and the presence of underlying neurodevelopmental genes) related to reward or inhibitory control which, when delayed or compromised, increases risk for substance abuse. How sensitive an endophenotype is to changing developmental influences and at what stage an endophenotype can be profitably used to index genetic risk remains largely unanswered, but as we will show for substance use and related disorders, identification appears possible by late childhood.
