Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity

Abstract

A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine–phosphate–guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36±10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36±7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.

Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study

“…However, accumulating evidence points to peripheral methylation patterns to constitute valid proxies for central processes (see, e.g., Ursini et al, 2011 ; Davies et al, 2012 ; Provencal et al, 2012 ). With regard to SLC6A4 , employing PET, methylation levels measured in peripheral cells were shown to be inversely related to 5-HT synthesis ( Wang et al, 2012 ) and 5-HTT availability ( Drabe et al, 2017 ) in the human brain, supporting the notion of peripheral SLC6A4 methylation to possibly mirror central processes.…”

Association of SLC6A4 methylation with long-term outcomes after stroke: focus on the interaction with suicidal ideation

“…The serotonin transporter is a key regulator of 5-HT levels, and its function is affected by epigenetic mechanisms including methylation of the SLC6A4 gene 21 , 40 . Hypermethylation of the SLC6A4 gene was associated with decreased SLC6A4 mRNA 13 , 21 , gene activity 40 , brain 5-HT synthesis 21 , and availiability 41 . Stroke patients with SLC6A4 hypermethylation might have reduced 5-HTT function and 5-HT availability, which would lead to decreased BDNF expression and thus suppress neurogenesis 42 , 43 and promote inflammation 44 .…”

“…Our findings suggest that methylation and SI might have synergistic effects on long-term stroke outcomes. Previously, suicidality was shown to be associated with low 5-HT 22 , and SLC6A4 hypermethylation would exacerbate any deficit in 5HT 21 , 41 . Furthermore, post-stroke depression (PSD) is a well-known risk factor for poor long-term stroke outcomes 52 , and SI after stroke is strongly associated with PSD 30 , 45 and SLC6A4 hypermethylation has been proposed as a diagnostic and prognostic biomarker for PSD 34 .…”

“…Furthermore, methylation status could be tissue specific, and SLC6A4 methylation in the present study was measured in the peripheral blood but not in the brain. However, the SLC6A4 hypermethylation status in the periphery affected low transcriptional activity of 5-HTT mRNA 21 and was associated with decreased brain 5-HT synthesis and availability 21 , 41 . Also, a previous investigation of nine CpGs which included all of CpG sites in the present analyses, revealed that increased methylation of the investigated region conferred decreased gene activity 40 .…”

Serotonin transporter promoter methylation in peripheral cells and neural responses to negative stimuli: A study of adolescent monozygotic twins

“…For instance, Wang et al 11 found that SLC6A4 promoter methylation in T lymphocytes of adults was associated with lower in vivo Positron Emission Tomography (PET) measures of brain serotonin (5-hydroxytryptamine; 5-HT) synthesis in the orbitofrontal cortex and higher childhood aggression. Furthermore, a recent study found associations between SLC6A4 methylation and in vivo PET measures of serotonin transporter availability 12 . We also previously reported that SCL6A4 methylation obtained from white blood cells was significantly associated with activation in response to negative emotional stimuli in the insula 13 and lower hippocampal volume 14 in depressed patients and controls.…”