Background: Across multiple mental health-related measures, a polymorphism (5-HTTLPR) within the promoter of the serotonin transporter gene has been associated with differential psychological sensitivity to stressful experiences. Yet, the specific mechanisms by which this polymorphism contributes to risk for psychological dysfunction is unclear. Therefore, we investigated cortisol reactivity to psychosocial stress as a potential intermediate phenotype that might predispose to such risk.

Methods: A psychologically healthy sample of 182 young adults were genotyped for the 5-HTTLPR. Each participant delivered a speech and performed mental arithmetic in one of three audience conditions: a critical evaluative audience, a supportive evaluative audience, or no audience. Salivary cortisol was sampled at baseline and at 20, 40, and 75 min after stressor onset.

Results: The two evaluative audience conditions elicited similar, significant increases in cortisol that were significantly greater than in the no audience control. Together, the evaluative audience conditions revealed a significant relationship between cortisol reactivity and the 5-HTTLPR, with the short/short genotype showing the greatest reactivity. Internal analyses revealed that the 5-HTTLPR was significantly associated with cortisol reactivity in the negative audience condition only, suggesting that short/short individuals might be especially vulnerable to social threat.

Conclusions: The short/short genotype of the 5-HTTLPR is associated with greater cortisol reactivity to social threat. When short/short individuals experience stressful life events, they might be at greater risk for the adverse psychological and physical health consequences associated with heightened cortisol exposure.