Epigenetic Modifications Associated with Low SES May Influence Depression Risk

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Socioeconomic status was the only environmental stressor that predicted an increase in SLC6A4 proximal promoter methylation.
Socioeconomic status was the only environmental stressor that predicted an increase in SLC6A4 proximal promoter methylation.

Specific stressors such as child abuse and nonspecific stressors such as low socioeconomic status (SES) have both been implicated in the risk for mental illness. Lower SES has been linked with elevated risk of depression, anxiety, and addiction, as well as poorer general health. These associations could be driven by a variety of factors, including higher stress levels, poor housing quality, and exposure to violence. 

A growing body of research shows that epigenetic modification may be one mechanism by which adverse experience influences the risk for mental illness. “Generally, relatively increased DNA methylation of gene promoters, which is most often associated with decreased gene expression, has been associated with exposure” to stressors, wrote the authors of a new study.

In particular, recent findings point to methylation of the serotonin transporter gene (SLC6A4) as a mechanism underlying this connection. Both specific and non-specific adverse experiences have been linked with methylation of several CpG sites within this gene, which in turn has been correlated with elevated symptoms of depression. Additionally, the authors previously found that “relatively increased SLC6A4 proximal promoter methylation is associated with increased threat-related amygdala reactivity, which not only has a central role in stress responsiveness but also is implicated in the etiology and pathophysiology of stress-related disorders including depression.”

However, these cross-sectional data do not indicate whether stress exposure may influence changes in methylation and whether this results in changes in brain function.

In the paper published in Molecular Psychiatry, researchers at Duke University investigated whether changes in gene methylation related to adversity contribute to the risk for depression. They hypothesized that stress exposure from childhood maltreatment, stressful life events, and low SES would be linked with increased SLC6A4 proximal promoter methylation from Wave 1 and Wave 2, when participants were aged 11-15 and 13-18, respectively. They further hypothesized that increased amygdala reactivity over the same time period would predict greater increases in depressive symptoms approximately 1 year later, when participants were aged 14-19.

To test these hypotheses, the authors examined longitudinal epigenetic, neuroimaging, and behavioral data from 132 adolescents with differential depression risk based on their family history of the disorder. According to their results, SES was the only environmental stressor that predicted an increase in SLC6A4 proximal promoter methylation, and this was not influenced by family history of mental illness.

Also consistent with their hypotheses, these changes predicted greater increases in threat-related amygdala reactivity from Wave 1 to Wave 2–independent of family history here, as well. Finally, the observed increases in amygdala reactivity predicted greater increases in depressive symptoms from at Wave 3, but only in participants with a positive family history for depression.

Future research efforts to identify environmental mechanisms influencing the observed effects of SES on methylation may highlight potential targets for intervention. In addition, identifying familial factors that influence the link between amygdala reactivity and depressive symptoms exclusive to adolescents with a family history of depression may further help narrow prevention efforts.

“Moreover, preventive interventions such as training in mindfulness-based techniques may be effective in lowering threat-related amygdala reactivity in adolescents identified as high risk due to increased SLC6A4 methylation,” the authors stated. “Thus, if replicated, the risk pathway identified here could represent a discrete biomarker that could be targeted by novel strategies for personalized treatment and prevention,” they concluded.


Swartz JR, Hariri AR, Williamson DE. An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents. Mol Psychiatry. 2016. doi: 10.1038/mp.2016.82.

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