P300 amplitude provides an illuminating example. Since its discovery by Sutton and colleagues in the 1960s (Sutton, Braren, Zubin, & John, 1965), the P300 component has undoubtedly been one of the most widely studied ERP components. The initial report more than 30 years ago by Begleiter and colleagues that P300 amplitude was reduced in alcohol-naïve boys at risk for alcoholism (Begleiter, Porjesz, Bihari, & Kissin, 1984) has motivated a large literature exploring the notion that P300 amplitude reduction is associated with alcoholism and other forms of disinhibitory psychopathology (i.e., childhood disruptive disorders, antisociality, substance use disorders, and related traits like impulsivity, aggression, poor decision making, etc.). This body of work has produced many empirical reports and several meta-analyses, which in aggregate suggest that P300 amplitude reduction is a robust candidate endophenotype for disinhibitory psychopathology and behavior. Yet we failed to find a single variant associated with it. We also failed to confirm any associations reported in previous candidate gene studies (Vaidyanathan, Malone, Miller, et al., 2014). Thus, although P300 is arguably one of the best validated endophenotypes identified to date (Miller & Rockstroh, 2013), it did not lead to robust genetic discovery.
