Developmental Endophenotypes: Indexing Genetic Risk for Substance Abuse with the P300 Brain Event-Related Potential

Although substance use disorders are heritable, their complexity has made identifying genes underlying their development challenging. Endophenotypes, biologically informed quantitative measures that index genetic risk for a disorder, are being recognized for their potential to assist the search for disorder relevant genes. After outlining criteria for an endophenotype that includes developmental considerations, we review how the brain P300 response serves as an index of genetic risk for substance abuse and related externalizing disorders. The P300 response is highly heritable and associated broadly with characteristics of externalizing disorder, including childhood disruptive disorders, antisociality, and precocious expression of deviant behavior. This association appears to be mediated by shared genetic influences. Prospective studies confirm that reduced P300 amplitude present in youth prior to significant exposure to addictive substances is associated with the subsequent development of substance use disorders. Despite pronounced change in mean level over the course of development, P300 amplitude shows strong rank order stability with repeated assessment through young adulthood. In addition, P300 developmental trajectories based on multiple assessments show very high heritability and may be especially informative as measures of genetic risk. Collectively, these findings provide strong support that P300 amplitude and its change through development reflect genetic vulnerability to substance abuse and related externalizing psychopathology.