According to our results, exposure either to RLE or CHA caused a marked, dose-dependent increase in all three depression-related phenotypes (Supporting Information and Fig. A in S1 File). However, 5-HTTLPR weakly modulated the effect of RLE on lifetime depression and current BSI-depression, while in BSI-anxiety it showed a weak main effect, namely a direct association with the risk s allele even in individuals having experienced low life stress, and stress exposure caused only a minor additional increase in anxiety. These weak genetic associations are in line with the hypothesis that depression and anxiety are highly polygenic and multifactorial disorders [2,13]. This is confirmed also by the GxG interaction effect of 5-HTTLPR with CB1 receptor gene promoter polymorphisms in the anxiety phenotype, and supported also by animal experiments in anxiety models [32,33]. The direct association of anxiety with the s allele was stronger in young (≤30) individuals. In addition, although CHA did not show any interaction with 5-HTTLPR on any of the phenotypes, it had an important influence on the 5-HTTLPRxRLE interaction. Namely, in young subjects it sensitized towards the effect
