Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.
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This work was supported by the National Institute on Alcohol Abuse and Alcoholism grant R01AA016274 and the Dielmann Family (DEW), MH087493 (Consuelo Walss-Bass, PhD), the National Institute on Drug Abuse grant R01DA033369 and R01DA031579 (ARH), the National Institute on Aging grant R01AG049789 (ARH) and the Center for the Study of Adolescent Risk and Resilience, NIH grant P30DA023026 (JRS). We thank Ryan Bogdan, Annchen Knodt and Caitlin Carey for assistance with conducting analyses and Yuliya Nikolova for discussions of the manuscript.
ARH and DEW designed the study; DEW oversaw analysis of DNA methylation; ARH and JRS oversaw analysis of functional imaging data; JRS conducted the statistical analyses and drafted the manuscript; all authors edited and approved the final manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Swartz, J., Hariri, A. & Williamson, D. An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents. Mol Psychiatry 22, 209–214 (2017). https://doi.org/10.1038/mp.2016.82
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