We examined epigenetic regulation in regards to behaviorally and clinically relevant human brain function. Specifically, we found that increased promoter methylation of the serotonin transporter gene predicted increased threat-related amygdala reactivity and decreased mRNA expression in postmortem amygdala tissue. These patterns were independent of functional genetic variation in the same region. Furthermore, the association with amygdala reactivity was replicated in a second cohort and was robust to both sampling methods and age.
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We thank B. Brigidi, K. Faig, A. Gorka, S. Jacobson, A. Knodt, B. Williams and K. Sugden for their assistance in DNS data collection and analysis, and J. Hanson for his assistance in figure preparation. The Duke Neurogenetics Study is supported by Duke University and National Institute on Drug Abuse grant DA03369. The Teen Alcohol Outcomes Study was supported by AA016274 and ongoing support from the Dielmann Family (D.E.W.). Y.S.N. receives support through a Howard Hughes Medical Institute International Student Research fellowship. A.R.H. receives support through National Institute on Drug Abuse grants DA033369 and DA031579. K.C.K. receives support through National Institute of Mental Health grants MH078928 and MH093612. E.S. receives support through National Institute of Mental Health grants MH084060 and MH077159.
The authors declare no competing financial interests.
Integrated supplementary information
PCR bias testing was performed by EpigenDx separately for the entire ADS580 assay (red line) and CpG 14 (blue line). Data are presented for the 0-100% (a) and 0-10% (b) range.
Supplementary Figure 2 Scatterplots depicting the correlations between PC1 and bilateral amygdala reactivity in the Discovery and Replication cohorts.
The top principal component capturing 24% of the variability in SLC6A4 proximal promoter methylation in the Discovery cohort was positively correlated with left amygdala reactivity (a) and predicted right amygdala reactivity at a trend-level (b). The top principal component capturing 30% of the variability in SLC6A4 proximal promoter methylation in the Replication cohort was positively correlated with left (c), but not right (d) amygdala reactivity. *p < 0.05, #p < 0.10
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Nikolova, Y., Koenen, K., Galea, S. et al. Beyond genotype: serotonin transporter epigenetic modification predicts human brain function. Nat Neurosci 17, 1153–1155 (2014). https://doi.org/10.1038/nn.3778
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