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

Abstract

Summary 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.

War Zone Stress Interacts With the 5-HTTLPR Polymorphism to Predict the Development of Sustained Attention for Negative Emotion Stimuli in Soldiers Returning From Iraq

“…Following informed consent, participants provided demographic information, completed questionnaires, and were interviewed for the presence of diagnoses based on the fourth edition, text revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association, 2000). Study procedures included a number of assessments that are not the focus of the current study but are reported elsewhere Beevers, Marti, et al, 2011;Josephs et al, 2012;Telch et al, 2013;Telch, Rosenfield, Lee, & Pai, 2012).…”

Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior

“…Examining the concomitant effects of another polymorphism (C1019G) from the serotonin receptor gene, 5HT1A and the Val66Met polymorphism of the BDNF gene revealed increased risk for depression when expressing both risk variants (61). In addition, carriers of the long allele with concomitant higher levels of testosterone showed lower cortisol secretion after threat indicating neuropsychiatric resilience for this combination in humans (62). A recent review on genetic association studies of suicidal behavior identified 5HTTLPR and BDNF among few others as most promising candidates (63).…”

Genetic and environmental modulation of neurotrophic and anabolic stress response: Counterbalancing forces

“…Testosterone is believed to exert neurotrophic effects, proposed to occur via aromatization to estradiol and/or by transformation into 5α-dihydrotestosterone [28]. Furthermore, testosterone is implicated in serotonin activation [54], and baseline testosterone is known to interact with 5HTTLPR S carriage to augment cortisol response to heterogeneous threats [55]. Clearly, potential roles of 5HTTLPR and prior trauma exposure in regulating testosterone stress response require further investigation.…”