rigorous replication studies are necessary to establish such interactions. As pointed by Milne et al. (2008), replication in additional independent samples of observed gene–gene interaction is crucial. In particular, caution should be exercised during the replication because differences of LD between different study populations such as AA and EA may have important impacts on the detection of high-order gene–gene interactions. Even when significant interactive effects are observed in a replication study, caution is necessary in elucidating exactly what constitutes a replicated result and the biological meaning of such replication. Therefore, ideally, observed gene–gene interactions should not only be replicated from a statistical perspective but also be validated experimentally from a biological perspective.
