Although we argue that the traditional approach to candidate gene studies is flawed, this does not necessarily mean that none of the traditional candidate genes will turn out to be robustly associated with psychophysiological endophenotypes. We are agnostic on this point, albeit somewhat skeptical. Amplitude of the event-related negativity (ERN) is associated with both internalizing and externalizing disorders (with different directions of effect). Several studies have demonstrated associations with candidate genes (summarized in Manoach & Agam, 2013). Nevertheless, as with P300 amplitude, another widely studied endophenotype, there have not been robust, validated findings. Models of ERN amplitude based in reinforcement learning hold that the ERN reflects phasic dopamine activity in response to an unexpected event or outcome (Nieuwenhuis, Holroyd, Mol, & Coles, 2004; Walsh & Anderson, 2012). This, of course, suggests that dopamine genes may influence ERN amplitude. To date, there has only been one replicated finding. Two studies have reported associations between ERN amplitude and a polymorphism of the DRD4 receptor gene (Agam et al., 2014; Kramer et al., 2007). However, whereas this SNP accounted for approximately 13% of
