Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Aug 8;8(1):147.
doi: 10.1038/s41398-018-0195-6.

Serotonin Transporter Promoter Methylation in Peripheral Cells and Neural Responses to Negative Stimuli: A Study of Adolescent Monozygotic Twins

Affiliations
Free PMC article

Serotonin Transporter Promoter Methylation in Peripheral Cells and Neural Responses to Negative Stimuli: A Study of Adolescent Monozygotic Twins

Elmira Ismaylova et al. Transl Psychiatry. .
Free PMC article

Abstract

Several studies have examined associations between peripheral DNA methylation patterns of the serotonin transporter gene (SLC6A4) promoter and symptoms of depression and anxiety. The SLC6A4 promoter methylation has also been associated with frontal-limbic brain responses to negative stimuli. However, it is unclear how much of this association is confounded by DNA sequence variations. We utilized a monozygotic-twin within-pair discordance design, to test whether DNA methylation at specific CpG sites in the SLC6A4 promoter of peripheral cells is associated with greater frontal-limbic brain responses to negative stimuli (sadness and fear), independently of DNA sequence effects. In total 48 pairs of healthy 15-year-old monozygotic twins from the Quebec Newborn Twin Study, followed regularly since birth, underwent functional magnetic resonance imaging while conducting an emotion-processing task. The SLC6A4 promoter methylation level was assessed in saliva samples using pyrosequencing. Relative to the co-twins with lower SLC6A4 promoter methylation levels, twins with higher peripheral SLC6A4 methylation levels showed greater orbitofrontal cortical (OFC) activity and left amygdala-anterior cingulate cortex (ACC) and left amygdala-right OFC connectivity in response to sadness as well as greater ACC-left amygdala and ACC-left insula connectivity in response to fearful stimuli. By utilising a monozygotic-twin design, we provided evidence that associations between peripheral SLC6A4 promoter methylation and frontal-limbic brain responses to negative stimuli are, in part, independent of DNA sequence variations. Although causality cannot be determined here, SLC6A4 promoter methylation may be one of the mechanisms underlying how environmental factors influence the serotonin system, potentially affecting emotional processing through frontal-limbic areas.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Greater within-pair difference in peripheral SLC6A4 promoter methylation was associated with greater responses to sad stimuli in left orbitofrontal cortex (T = 5.11, pFWE = 0.032).
The color bar represents T values
Fig. 2
Fig. 2. Connectome ring representation of ROI-to-ROI connectivity between amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and insula in the sad condition.
Only significant connectivity discordances are represented: greater ROI-to-ROI connectivity in the sad condition for twins with greater methylation level compared to their co-twins with lower methylation level, between left amygdala and ACC (T = 1.83, p = 0.036), as well as between left amygdala and right OFC (T = 1.71, p = 0.047). The color bar represents T values. The bars plot in the top right-hand corner represents differences in effect sizes (difference in Fisher-transformed correlation coefficients) between twins with greater methylation level and their co-twins with lower methylation level, for each connection
Fig. 3
Fig. 3. Connectome ring representation of ROI-to-ROI connectivity between anterior cingulate cortex (ACC), left amygdala and insula in the fearful condition.
Only significant connectivity discordances are represented: greater ROI-to-ROI connectivity in the fearful condition for twins with greater methylation level: between ACC and left amygdala (T = 2.79, p = 0.004), as well as between ACC and left insula (T = 1.85, p = 0.035). The color bar represents T values. The bars plot in the top right-hand corner represents differences in effect sizes (difference in Fisher-transformed correlation coefficients) between twins with greater methylation level and their co-twins with lower methylation level, for each connection

Similar articles

See all similar articles

Cited by 3 articles

References

    1. McGowan PO, Szyf M. The epigenetics of social adversity in early life: implications for mental health outcomes. Neurobiol. Dis. 2010;39:66–72. doi: 10.1016/j.nbd.2009.12.026. - DOI - PubMed
    1. Razin A. CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J. 1998;17:4905–4908. doi: 10.1093/emboj/17.17.4905. - DOI - PMC - PubMed
    1. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21. doi: 10.1101/gad.947102. - DOI - PubMed
    1. Thakore PI, Black JB, Hilton IB, Gersbach CA. Editing the epigenome: technologies for programmable transcriptional modulation and epigenetic regulation. Nat. Methods. 2016;13:127–137. doi: 10.1038/nmeth.3733. - DOI - PMC - PubMed
    1. Razin A, Cedar H. DNA methylation and embryogenesis. EXS. 1993;64:343–357. - PubMed

Publication types

Substances

Grant support

Feedback