Abstract
The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been implicated in moderating vulnerability to stress-related psychopathology upon exposure to environmental adversity. A recent meta-analysis suggests a potential biological pathway conveying genotype-dependent stress sensitivity by demonstrating a small, but significant association of 5-HTTLPR and cortisol stress reactivity. An arguably more potent approach to detect larger effects when investigating the 5-HTTLPR stress sensitivity hypothesis is to account for both genetic and epigenetic variation in the serotonin transporter gene (SLC6A4). Here, we applied this approach in an experimental setting. Two hundred healthy adults were exposed to a laboratory stressor (Trier Social Stress Test) and cortisol response patterns were assessed as a function of 5-HTTLPR and DNA methylation profiles in SLC6A4. Specifically, we analyzed 83 CpG sites within a 799-bp promoter-associated CpG island of SLC6A4 using a highly sensitive bisulfite pyrosequencing method. Our results suggest that SLC6A4 methylation levels significantly moderate the association of 5-HTTLPR and cortisol stress reactivity. For individuals displaying low levels of SLC6A4 methylation, the S allele relates to increased cortisol stress reactivity in a dose-dependent fashion accounting for 7–9% of the variance in the endocrine stress response. By contrast, no such effect occurred under conditions of high SLC6A4 methylation, indicating that epigenetic changes may compensate for genotype-dependent differences in stress sensitivity. Studying epigenetic markers may advance gene–environment interaction research on 5-HTTLPR as they possibly capture the net effects of environmental influences relevant for stress-related phenotypes under serotonergic control.
Highlights
Altered regulation of the hypothalamus–pituitary adrenal (HPA) axis, one of the body’s major stress systems, has been implicated as a correlate or even causal factor for a broad range of stressrelated psychiatric disorders.[1]
Mean SLC6A4 methylation levels were comparable between groups separated by 5-HTTLPR genotype (F1,182 = 0.12, P = 0.89)
For individuals displaying low levels of SLC6A4 methylation, the S allele relates to increased cortisol stress reactivity in a dosedependent fashion, whereas no such effect occurred when SLC6A4 methylation was high
Summary
Altered regulation of the hypothalamus–pituitary adrenal (HPA) axis, one of the body’s major stress systems, has been implicated as a correlate or even causal factor for a broad range of stressrelated psychiatric disorders.[1]. Received 22 July 2014; accepted 25 July 2014 methylation at 1 out of the 12 CpG sites studied in bullied twins 5-HTTLPR genotyping which in turn was related to a blunted cortisol stress response Such epigenetic recalibration of the neuroendocrine system presumably reflects a flexible adaption to environmental demands, but may convey disease vulnerability if the programmed response is not adequate anymore.[34]. To test for effects of 5-HTTLPR, SLC6A4 methylation (mean methylation levels across the 83 CpG sites) and their interaction on cortisol reactivity, mixed-design analyses of covariance with repeated measures (cortisol samples) and baseline cortisol values as covariate were conducted.
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