Specifically, are we using a threshold to determine when an interaction is real, or using a threshold more broadly to determine whether interactions are noteworthy and merit further follow-up? Additionally, there was concern that a statistical threshold may represent too stringent a standard, particularly if thresholds are the only standard. For example, in a multi-stage GWAS and replication joint analysis of 10,519 bladder cancer cases and 13,218 controls, the p-value for interaction between ever/never smoking and the NAT2 tag SNP rs1495741 was only 2.8×10−4, clearly not fulfilling any “genome-wide significant” threshold [Rothman, et al. 2010]. However, this interaction is widely accepted because of underlying biology and consistency in replication. This example is not being used to advocate low thresholds; however, it demonstrates that very large sample sizes are needed to detect interactions using only highly stringent significance thresholds.
