A susceptibility gene for affective disorders and the response of the human amygdala

Background: A common regulatory variant (5-HTTLPR) in the human serotonin transporter gene (SLC6A4), resulting in altered transcription and transporter availability, has been associated with vulnerability for affective disorders, including anxiety and depression. A recent functional magnetic resonance imaging study suggested that this association may be mediated by 5-HTTLPR effects on the response bias of the human amygdala-a brain region critical for emotional and social behavior-to environmental threat. Objectives and Design: To examine the effects of 5-HTTLPR genotype on the reactivity of the human amygdala to salient environmental cues with functional magnetic resonance imaging in a large (N = 92) cohort of volunteers carefully screened for past and present medical or psychiatric illness, and to explore the effects of 5-HTTLPR genotype as well as amygdala reactivity on harm avoidance, a putative personality measure related to trait anxiety. Results: We now confirm the finding of 5-HTTLPR short allele-driven amygdala hyperreactivity in a large independent cohort of healthy subjects with no history of psychiatric illness or treatment. Furthermore, we demonstrate that these genotype effects on amygdala function are consistent with a dominant short allele effect and are equally prominent in men and women. However, neither 5-HTTLPR genotype, amygdala reactivity, nor genotype-driven Variability in this reactivity was reflected in harm avoidance scores. Conclusions: Our results reveal a potent modulatory effect of the 5-HTTLPR on amygdala reactivity to environmental threat. Since this genetically driven effect exists in healthy subjects, it does not, in and of itself, predict dimensions of mood or temperament. As such, the 5-HTTLPR may represent a classic susceptibility factor for affective disorders by biasing the functional reactivity of the human amygdala in the context of stressful life experiences and/or deficient cortical regulatory input.