stressful life events on risk of depression and suicidal behavior.90 Carriers of the low-transcribing S allele exhibited more depression and suicidality after stressful life events than L individuals with two copies of the allele.90 Although a meta-analysis failed to support this G × E interaction,91 other metanalyses have, and multiple lines of evidence support a role for HTTLPR regulation of emotion and response to stress. In particular, HTTLPR has been shown to influence the activity of the amygdala, a brain region that regulates emotional response to environmental changes and that is involved in the pathogenesis of depression and anxiety. Both adults41 and children92 carrying the low-activity s allele displayed increased amygdala reactivity to fearful stimuli, reduced amygdala volume,93 and enhanced functional coupling between the amygdala and the ventro medial prefrontal cortex,94 a brain region that ordinarily represses amygdala activation. In addition, HTTLPR appears to predict stress-induced cortisolrelease.95 HTT gene × environment interactions have also been observed in animal models. The rhesus macaque has an orthologous polymorphism (rh-5HTTLPR) in the promoter region of serotonin transporter gene. In these animals, early life stress exposure led to dyscontrolled behavior and enhanced stress response later in life (for review see Ref.96). Consistent with findings
