The answer is: in the stress system. Stress reactivity might be an important link between a genetic variant of the serotonin transporter gene, stressful life events in early years and depression.
There is evidence of interaction between a functional genetic variant of the serotonin transporter gene and life events. Depression is not based on a simple gene or a cluster of genes. But on a gene and environment interaction. So the risk of getting a depression is higher when a certain genetic variant of the serotonin transporter gene is present in the presence of life stress, especially in early life. But how does this genetic predisposition and life stress lead to depression?
Cortisol, a reliable indicator of hypothalamic pituitary-adrenocortical (HPA) axis functioning and stress reactivity has a hereditary component and is also elevated in 40%–60% of adults diagnosed with depression.
How was this research done?
Girls at high (n=25) and low (n=42) risk for depression by virtue of the presence or absence of a family history of this disorder were genotyped and exposed to a standardized laboratory stress task. Forty-two girls had biological mothers with no current or past Axis I disorder (low-risk daughters), and 25 girls had biological mothers with a history of recurrent episodes of depression during their daughter’s lifetime (high-risk daughters). Cortisol levels were assessed before the stressor, after the stressor,and during an extended recovery period.
The two groups of daughters did not differ significantly in their genotype distribution.
And the results?
Daughters who are homozygous for the s allele showed a marked increase in cortisol production during and following exposure to the stressor. In contrast, daughters with at least one copy of the l allele exhibited a slight decrease in cortisol production over the course of the stress session.See the figure.
These results explain in part why stress in some people can lead to depression and not in others. This is not a black and white outcome. Some people without the s allele can also get a depression but usually with a lot more stress compared to those with a s allele. Probably these findings can't explain everything about the origins of depression but these findings sound plausible. They probably only apply to certain depressions such as melancholic depression and they probably differ based on ethnicity but nevertheless these results are encouraging to my opinion.
Research into how the serotonin system plays a role in regulating HPA axis activity might shed some light on further mechanisms.
Biological stress reactivity is a plausible mechanism underlying the association between genotype and exposure to life stress in predicting the onset of depression.
In the future it might be possible to discover high risk individuals and develop treatment or prevention programs.
Serotonin and the transporter gene
Serotonin is an important neurotransmitter believed to play an important role in depression. The transport of serotonin during reuptake in the neuron from the synaps is done by a protein. The production of this protein is dependent on certain genes. The variant of this gene affects how much serotonin transporter protein is produced. Individuals with the short allelic form of this variant showed an increased risk of depression compared to those carrying the long allele but only when exposed to adverse life events or maltreatment. There have been some nonreplications, but these have been outnumbered by the number of replicated findings. The original science abstract of the article on influence of life stress on depression is freely available
GOTLIB, I., JOORMANN, J., MINOR, K., HALLMAYER, J. (2007). HPA Axis Reactivity: A Mechanism Underlying the Associations Among 5-HTTLPR, Stress, and Depression. Biological Psychiatry DOI: 10.1016/j.biopsych.2007.10.008