In the current study on participants with experiences of loss or other traumatic events, the 5HTTLPR genotype association with unresolved state of mind was dependent on methylation density. As expected, the long variant in combination with high methylation levels of the 5HTT promoter associated CpG islands predicted more unresolved loss or trauma. Methylation of alleles carrying the ll
5HTT variant seemed to hamper the expression of the otherwise protective ll
) and to elevate the risk of unresolved responses to loss or other trauma. The short variant of 5HTT predicted more unresolved loss or trauma, but only when levels of methylation were low. Surprisingly, higher levels of methylation of the ss
variant were associated with less unresolved loss or other trauma indicating less negative affect about the traumatic experience. This suggests a discontinuous effect of greater methylation for those with the ss
genotype, perhaps manifesting in decreased preoccupation and a different pattern of adjustment to trauma.
DNA methylation is an important determinant of gene expression, and it should therefore be taken into account when associations of DNA sequences with psychological problems are examined (15
). Methylation of CpG islands may repress gene expression in some tissues, whereas the absence of methylation of such a site in other tissues corresponds with increased mRNA transcription. Methylation is found to be a common biological process influenced by environmental stressors such as abusive parenting (19
). Beach et al. (2009) found that childhood experiences of sexual or physical abuse increased the level of methylation at 5HTTLPR. Child maltreatment has long-term developmental consequences (19
), which suggests that methylation may serve as the interface between adverse environment and the developing organism. Future studies should focus on how the environment affects methylation patterns.
In an earlier study on methylation of the CpG islands in 5HTT, mRNA levels were significantly associated with level of methylation, but only if the influence of the 5HTTLPR genotype was controlled (8
). The authors argued that 5HTT levels are tightly regulated and the counteracting effects of methylation on genetic variation may be an adaptive mechanism to maintain a desired level of gene transcription. The vulnerability of the ss
variant of 5HTT for the development of psychological problems in response to adverse events may be lessened by higher levels of methylation. This may lower the risk for unresolved loss or trauma in carriers of the short variant of the serotonin transporter gene, entailing adaptive value.
A limitation of the study is that transformed cell lines were used and these sometimes can display markedly different methylation signatures than their cognate precursors. Fortunately, Grafodatskaya and colleagues demonstrated a high correlation (r
=.95) between lymphocyte DNA methylation and low passage lymphoblast DNA methylation (20
). Another limitation is sample size, and replication in larger samples and in other ethnicities is needed to confirm the generalizability of our findings.
Our findings suggest that associations between 5HTTLPR polymorphisms and psychological problems are significantly altered by environmentally induced methylation patterns. By ignoring methylation, researchers may fail to find or replicate ubiquitous G×E-interactions (15
). Some G×E effects may in fact be environmental influences mediated by methylation patterns.