The pattern of findings reported here both provides an explanation for the results of studies documenting associations among genotype, exposure to stress, and probability of depression, and extends our understanding of the relation between the 5-HTTLPR polymorphism and stress reactivity. Investigators have known for decades that exposure to severe life stressors increases the likelihood of subsequent depression (35
). We also know, however, that many individuals who experience life stress do not develop depression. Addressing this issue, there is now a growing literature demonstrating higher rates of depression among individuals with at least one copy of the short allele of the 5-HTTLPR polymorphism with increasing exposure to stressful life events than among individuals who are homozygous for the long allele. In particular, Kendler et al. (10
) found that individuals with two copies of the short allele were more likely than were their counterparts with two long alleles to become depressed in response to “common, low-threat events.” Although Kendler et al. hypothesized, based on these data, that this genetic polymorphism produces an increased sensitivity to the impact of stressful events that in turn increases the likelihood of depression, they could not explicitly examine this formulation with their data.
The findings presented in this paper demonstrate for the first time in a sample of young individuals that biological stress reactivity may be a critical mechanism underlying the association between the serotonin transporter gene and exposure to stressful events in increasing risk for depression. Although investigators have recognized the relation between the serotonin system and depression, only recently have they focused on the link between serotonin and stress. In fact, several lines of evidence now suggest that the serotonin system plays an important role in regulating HPA-axis activity. For example, researchers have now documented involvement of serotonin neurotransmission in both activation and feedback control of the HPA axis (36
). More specifically, investigators have demonstrated in animals that serotonin activates the HPA axis by stimulating CRF release, triggering ACTH release, and stimulating corticosteroid secretion (37
). Indeed, serotonin has been found to enhance the negative feedback control of cortisol (38
). Moreover, as we noted earlier, mice with the serotonin transporter gene knocked out have been found to exhibit increased HPA-axis response to acute stress (9
). Finally, Barr et al. (39
) examined the interactive influence of variation in the serotonin transporter gene promoter region and rearing condition on endocrine responses to stress in infant rhesus macaques. These investigators found that animals with one copy of the s
allele raised by peers had higher levels of ACTH during separation than did both l
animals and animals with an s
allele that were raised maternally, indicating that serotonin transporter gene variation affects HPA-axis activity, and that the influence of 5-HTTLPR on hormonal responses during stress is modulated by early experience.
It is noteworthy that while daughters with s
allele polymorphisms in this study were both less reactive to stress than were homozygous s
-allele carriers, they did not differ significantly from each other; that is, the s
daughters were not more reactive than were their l
counterparts. Studies of the interaction of genotype with a history of severe life stress have generally found a step function, in which having one short allele is associated with greater risk for depression than is having two long alleles, and being homozygous for the short allele confers the highest risk (5
). This is the first study to examine cortisol levels in response to a laboratory stressor as a function of genotype. It may be that, in contrast to cumulative severe life events, a single laboratory stressor is too mild, transient, and circumscribed to elicit cortisol production in l
individuals, but sufficient to provoke a cortisol response in s
participants. Thus, individuals who are homozygous for the short allele may have a lower threshold for cortisol production in response to stress than do their peers. Indeed, this formulation is consistent with Kendler et al.’s (10
) finding that individuals with two copies of the short allele were more likely than were their counterparts with two long alleles to become depressed in response to what they referred to as “common, low-threat events.” Studies designed to manipulate stress level parametrically would be valuable in examining this formulation more explicitly.
In closing, we have demonstrated in this study that biological stress reactivity is a plausible mechanism underlying the association between genotype and exposure to life stress in predicting the onset of depression. A notable strength of this study is that the results are not confounded with a history of depression; indeed, none of the participants had experienced any previous Axis-I disorder. It will be important to follow this sample to examine the utility of genotype, family history, and stress reactivity in predicting the development of disorder. Our results underscore the importance of the relation between the 5-HTTLPR polymorphism and HPA-axis functioning in leading to emotional disturbance. It is critical, therefore, that investigators continue to work to elucidate the nature of this association so that we can develop programs and procedures that may prevent the occurrence of psychiatric disorders in high-risk individuals.