The largest limitation to the analyses presented here, however, is likely to come from the modest size of the effects reported for each of these phenotypes (with the exception of the APOE influences in Alzheimer’s disease, of course). In each polygenic disorder, replication of effects of polygenic loci is unlikely to be sufficiently robust that each study will provide nominally-significant observations. Final confidence in true effects requires both replication and generalization, including studies of more and more samples with the phenotypes that we study in the present review. However, we also need to display caution in considering the significance of apparent nonreplications. Recent analyses underscore the role that heterogeneity can play in engendering false-negative results from attempts at replication [126].
