were computed separately for the two sample halves. This approach, unlike the primary analyses, makes no assumptions about the scale of the putative interaction variable (i.e., does not assume that genetic effect sizes scale multiplicatively with AOS). Parameter estimates indicate that some interactions are synergistic; i.e., the main effect estimate at the sample median for environmental risk (onset of smoking at age 16) is in the same direction as the interaction odds ratio. In other words, SNP effects are stronger in earlier onset smokers. This was the case for GRIN2B (rs890), MAP3K4 and AGPAT4 (which is in LD with MAP3K4). In the cases of CHRNA5, KCNJ6 and IREB2 (in the flanking region of CHRNA5), the main effect and interaction odds ratios were in opposite directions (SNP effects stronger in later-onset smokers). Other cases of significant interactions were ambiguous, i.e., the main effect odds ratio was not significant at the median value for AOS; including GRIN2B (rs17760877), DBI, ADCY8, VAPA and GABRR1.
