We recognize that an endophenotype approach shares some of the same weaknesses as large-scale genotyping efforts. One is the issue of reliability. As noted by Kendler and Neale [114], although many candidate endophenotypes may seem scientifically “harder” (because they involve, for example, measures of brain structure) than “softer” clinical diagnoses, they do not necessarily have higher reliabilities. This ultimately impacts the power of one’s analyses, and in this respect it does not appear that endophenotypes offer a particular advantage over diagnoses. A second is the issue of whether candidate endophenotypes are truly less heterogeneous than diagnostic categories; for example, a reduction in P3 amplitude can result from several possible differences in underlying event-related oscillations. Thus, whether some endophenotypes for AUD are more homogenous than the diagnostic category for genetic analysis remains an open question. A third is the issue of replication. Only a few of the genes and genetic variants identified in Table 2 have replicable associations with their respective candidate endophenotypes and with AUD, and thus the replicable yield of AUD-associated genes remains small.
