Substantial evidence from over two decades of research supports the model presented in Figure 2 with P3AR emerging as a solid candidate endophenotype for the development of externalizing psychopathology. This includes key findings that: 1) a wide array of externalizing problems show P3AR, 2) P3AR is present in at-risk offspring in preadolescence, 3) those who engage in substance misuse and develop SUDs show P3AR earlier in life, 4) the unaffected co-twins of alcohol dependent twins have P3AR, and 5) the association between P3AR and externalizing reflects the influence of shared genetic effects. Although P300 amplitude diminishes with age, it shows high rank order stability, and the trajectory of change in P300 amplitude is itself heritable and reflective of underlying genetic risk for behavioral disinhibition. Molecular genetic investigations designed to identify the genes influencing P300 are underway. Such studies are likely to be enriched by adopting a developmental perspective that takes into account trajectories of change in P300 amplitude which are not only associated with risk for developing SUDs, but are also more highly heritable than single session measures of P3AR or any of the clinical phenotypes with which it is associated.
