Dataset Information

Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5-HTTLPR/rs25531 Polymorphism, and Stress.

ABSTRACT: DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional face-matching task. Individual SLC6A4 AluJb methylation profiles were ascertained and associated with MDD, amygdala reactivity, 5-HTTLPR/rs25531, and stress. SLC6A4 AluJb methylation was significantly lower in MDD compared to HC and in stressed compared to less stressed participants. Lower AluJb methylation was particularly found in 5-HTTLPR/rs25531 risk allele carriers under stress and correlated with less depressive episodes. fMRI analysis revealed a significant interaction of AluJb methylation and diagnosis in the amygdala, with MDD patients showing lower AluJb methylation associated with decreased amygdala reactivity. While no joint effect of AluJb methylation and 5-HTTLPR/rs25531 existed, risk allele carriers showed significantly increased bilateral amygdala activation. These findings suggest a role of SLC6A4 AluJb methylation in MDD, amygdala reactivity, and stress reaction, partly interwoven with 5-HTTLPR/rs25531 effects. Patients with low methylation in conjunction with a shorter MDD history and decreased amygdala reactivity might feature a more stress-adaptive epigenetic process, maybe via theoretically possible endogenous antidepressant-like effects. In contrast, patients with higher methylation might possibly suffer from impaired epigenetic adaption to chronic stress. Further, the 5-HTTLPR/rs25531 association with amygdala activation was confirmed in our large sample.

SUBMITTER: Schneider I

PROVIDER: S-EPMC5916353 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Publications

Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5-HTTLPR/rs25531 Polymorphism, and Stress.

Schneider Ilona I Kugel Harald H Redlich Ronny R Grotegerd Dominik D Bürger Christian C Bürkner Paul-Christian PC Opel Nils N Dohm Katharina K Zaremba Dario D Meinert Susanne S Schröder Nina N Straßburg Anna Milena AM Schwarte Kathrin K Schettler Christiane C Ambrée Oliver O Rust Stephan S Domschke Katharina K Arolt Volker V Heindel Walter W Baune Bernhard T BT Zhang Weiqi W Dannlowski Udo U Hohoff Christa C

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20171107 6

DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional f ...[more]

PMID: 29114103

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Project description:BACKGROUND: There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on micro-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders. RESULTS: At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression. CONCLUSION: This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.

Dataset Information

Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5-HTTLPR/rs25531 Polymorphism, and Stress.

Publications

Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5-HTTLPR/rs25531 Polymorphism, and Stress.

Similar Datasets

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