448 SNPs with p<0.05 in the interaction model, vs. 268 in the main-effect model). The increased number of low p-values may stem in part from overfitting, resulting from the additional degree of freedom to the model. However, the addition of alternative interaction terms to the model (Equation 3), including randomly reassigned rAOS (permuted AOS, designated pAOS; i.e., SNP x pAOS), age-at-first cigarette (SNP x rAFC), age-at-onset of drinking (SNP x rAOD) and age-at-first drink (SNP x rAFD) yielded fewer nominally significant p-values than the SNP x rAOS model and, in many cases, the main-effect model. (The age-at-onset variables rAFC, rAOD, and rAFC correlate with rAOS with R=0.67, R=0.26 and R=0.18, respectively). False-discovery rate analysis π0 parameters, derived from each of the complete p-value distributions, also suggest that incorporation of the SNP x rAOS interaction yields more overall findings than the main effect or alternative interaction models (Table 1).
