Dysfunction of the serotonin (5-hydroxytryptophan, 5-HT) system is implicated in mood disorders, and variation within serotonergic genes has been associated with negative emotional traits such as neuroticism and harm avoidance (3).
For example, higher scores in these traits are associated with a common short variant of a repetitive sequence in the transcriptional control region of the 5-HT transporter gene (-linked polymorphic region, 5-HTTLPR) is associated with higher levels of neuroticism or harm avoidance (5, 6).
Although neuroticism itself is a risk factor for depression (7), the link between 5-HTTLPR genotype and depression has been more tenuous, suggesting that 5-HTTLPR genotype does not have a consistent main effect on depression but instead may be moderated through other variables (8).
The effect of life stress on depression is moderated by a repeat length variation in the transcriptional control region of the serotonin transporter gene, which renders carriers of the short variant vulnerable for depression.
We investigated the underlying neural mechanisms of these epigenetic processes in individuals with no history of psychopathology by using multimodal magnetic resonance-based imaging (functional, perfusion, and structural), genotyping, and self-reported life stress and rumination.
Based on functional MRI and perfusion data, we found support for a model by which life stress interacts with the effect of serotonin transporter genotype on amygdala and hippocampal resting activation, two regions involved in depression and stress.
Life stress also differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features, and affected individuals' level of rumination.
They found that carriers of the 5-HTTLPR short variant showed more depressive symptoms, diagnosed depression, and suicidality as a function of stressful life events than individuals homozygous for the 5-HTTLPR long variant, thus demonstrating a significant gene-by-environment (Gx E) interaction.
Several replication studies also have reported a moderating effect of 5-HTTLPR genotype on the effect of life stress on depression (10, 11), although some reported an effect only in females (12, 13), and others failed to find any significant Gx E interaction (14, 15).It is possible that methodological differences in subject selection account for some inconsistencies across studies or that clinical assessments or measures of self-report are not sensitive enough to reveal a Gx E interaction reliably.These interactions may constitute a neural mechanism for epigenetic vulnerability toward, or protection against, depression.Adverse life events can reveal profound interindividual differences, rousing resilience in some and exposing susceptibility to mood disorders, including depression, in others.Diathesis-stress models have sought to explain these individual differences in terms of genetic predispositions interacting with environmental factors (1).Behavioral genetic studies have supported these models (2), with current work focusing on molecular and neural mechanism that may underlie these associations.