Related to the issue of replication, several of the genes summarized in Table 2 were selected based on their prior association with AUD-related phenotypes. This raises the question of whether studies of candidate endophenotypes have identified novel genes for AUD. Let us put the issue of novelty into context. GABRA2 exemplifies the success of an endophenotype approach for AUD in that variation in this gene was initially associated with a neurophysiological endophenotype [23] and numerous subsequent studies have documented its association with alcohol dependence [115]. On the other hand, the largest genome-wide association study of alcohol dependence to date [116] produced associations for genes implicated in alcohol metabolism that were initially identified in the early 1990s [117], as well as a handful of other genetic variants for which the replication results were mixed. Thus, in the absence of other, more successful approaches for AUD gene identification (both in terms of novelty and replicability), it seems reasonable that pursuing both large-scale genotyping strategies and endophenotypes-based approaches may be the most prudent path forward.
