Genetic and hormonal sensitivity to threat: testing a serotonin transporter genotype × testosterone interaction

Abstract

Background: Striking parallels are observed when comparing the literature on the 5-HTTLPR of the serotonin transporter gene (SLC6A4) to the testosterone (T) literature on measures of stress reactivity and neural activity. Short (S) allele carriers and individuals higher in testosterone levels show exaggerated stress responses, amygdala hyperactivity, and reduction of amygdala-prefrontal cortex coupling when exposed to threat.

Methods: Three studies tested the hypothesis that higher T, S carriers would show increased cortisol responses to threat.

Results: Supporting the hypothesis, a T × 5-HTTLPR interaction was obtained across all studies. Threats to status via social exclusion (Study 1), cognitive/perceptual failure (Study 2), and physical competence (Study 3) all produced elevated cortisol levels in S carriers with higher T levels. An unexpected result was that 5-HTTLPR long (L) allele homozygotes with higher T showed lower cortisol levels in response to threat-a pattern of response that closely parallels that reported for psychopathic individuals. Finally, combining effect sizes across studies showed that the likelihood that these effects were due to Type 1 errors was quite low.

Conclusions: What emerges from these studies is a novel yet reliable, and synergistic relationship between 5-HTTLPR genotype and testosterone on stress reactivity, possibly conferring vulnerability for multiple neuropsychiatric disorders.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Interaction of testosterone (standardized) by 5-HTTLPR on cortisol change in response to a social exclusion threat. Higher tesosterone is associated with higher cortisol stress response among S carriers (green line), whereas higher testosterone is associated with lower cortisol stress response among L homozygotes (red line).

Figure 2

Interaction of testosterone (standardized) by 5-HTTLPR on cortisol change in response to a cognitive/perceptual threat. Higher tesosterone is associated with higher cortisol stress response among S carriers (green line), whereas higher testosterone is associated with lower cortisol stress response among L homozygotes (red line).

Figure 3

Interaction of testosterone (standardized) by 5-HTTLPR on cortisol change in response to a physical threat. Higher tesosterone is associated with higher cortisol stress response among S carriers (green line), whereas higher testosterone is associated with lower cortisol stress response among L homozygotes (red line).