The best-studied gene-environment interaction involves a naturally occurring variation in the promoter of the human serotonin transporter gene (5-HTTLPR; also known as SLC6A4). The short allele of 5-HTTLPR is associated with decreased serotonin transporter availability and a resulting lower reuptake of serotonin from synaptic clefts. Carriers of the short allele show elevated risk for depression on exposure to stressful life events, including childhood maltreatment, compared with long-allele homozygotes in some but not all studies46–48. A recent meta-analysis has called into question whether this reported gene-environment interaction truly modifies risk for major depression given the limited sample sizes used in the studies49. Functional brain imaging studies have demonstrated increased amygdala reactivity to environmental threat50 and decreased coupling between the amygdala and the regulatory perigenual cingulate region51 in short-allele carriers, representing likely biological markers of increased susceptibility to stress in these individuals. These findings were confirmed in another recent meta-analysis, with this polymorphism accounting for up to 10% of phenotypic variance52. A recent study found an association between the long allele of 5-HTTLPR and emotional resilience in college students53.
