Several limitations of the present study have to be considered. First, caution must be exercised in the interpretation of life stress, as it is difficult to separate the effect of environmental factors from genetic liability. Studies using genetically sensitive designs have indicated that many supposed environmental effects actually in part reflect genetic factors [42]. Thus, exposure to life events may be genetically mediated and the gene-environment interaction observed in this study might well be due to interactions between the PER2 gene and other anonymous genes that were not identified (gene-gene interaction). Also in our study, the genotype groups differed slightly in their load of negative life events (see Table 1). However, as these differences are not statistically significant, and as the main effect of genotype is included in the regression model revealing the interaction effect, we do not assume the GxE effect to reflect merely a gene-environment-correlation. Second, another point of criticism may be the fact that the design of the present study is not completely longitudinal, with the interval of the life events between 15 and 19 years overlapping
