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Beyond genotype: serotonin transporter epigenetic modification predicts human brain function


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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Figure 1: Effects of SLC6A4 promoter methylation on amygdala reactivity.
Figure 2: Effects of SLC6A4 promoter methylation on gene expression.

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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.

Author information




Y.S.N. designed the study, participated in the collection of the neuroimaging and genetic data for the discovery cohort, conducted all of the statistical analyses, and wrote the manuscript with A.R.H. K.C.K. and S.G. designed and coordinated the methylation analyses in the discovery cohort. C.-M.W. developed and performed the methylation assays in the replication and postmortem cohorts. M.L.S. conducted the quantitative PCR in the postmortem cohort. E.S. designed the parent protocol, supervised quantitative PCR experiments and coordinated methylation analyses in the postmortem cohort. D.E.W. designed the parent protocol for the replication cohort and coordinated the methylation assays in both the replication and postmortem cohorts. A.R.H. designed the study, coordinated all analyses and wrote the manuscript with Y.S.N. He also designed the parent protocol for the discovery cohort and the neuroimaging protocol for the replication cohort. All of the authors provided feedback on the manuscript and approved its final version.

Corresponding author

Correspondence to Yuliya S Nikolova.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 SLC6A4 methylation assay PCR bias testing.

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 and Supplementary Tables 1–6 (PDF 1522 kb)

Supplementary Methods Checklist

(PDF 395 kb)

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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).

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