5-HTTLPR与抑郁相关性的研究动态

The Recent Progress in the Research on Association Between 5-HTTLPR and Depression

本文对5-HTTLPR与抑郁关系的相关研究进行了综述。5-HTTLPR基因型并不直接影响抑郁的发生,而是通过基因与环境交互作用影响的。携带有S等位基因的个体暴露于较多的负性生活事件时,更易发生抑郁。另外,5-HTTLPR还与CYP2C9、BDNF等基因存在交互作用。研究发现5-HTTLPR对抑郁作用的机制可能有两条。首先,和基因型为L/L的个体相比,携带有S等位基因的个体的杏仁核脑区的活动增强,而前额叶-杏仁核神经环路的耦合相对较弱。其次,携带有S等位基因的个体在应激条件下HPA轴活性更强,有更高的皮质醇含量,进而更容易抑郁。总结前人的研究发现,5-HTTLPR通过影响情绪加工的脑区以及参与应激反应的HPA轴活性而使个体具有不同的易感性,有较高易感性的个体(携带S等位基因)在较高的应激条件下或者其他易感基因型存在时就会发生抑郁。

In recent years, a great number of studies have demonstrated the interacting effect between 5-HTTLPR, a length polymorphism in the serotonin transporter gene, and environmental adversity on depression. This review systematically discussed researches on the association between 5-HTTLPR and depression, and 5-HTTLPR×Environment interaction. Neuroimaging and neuroendocrinological studies examining the mechanisms underlying the 5-HTTLPR×Stress interaction and the Gene×Gene×Environment interactions were further discussed. In this review, we began with association studies linking 5-HTTLPR genotype and depression in both animal models and human studies. Although the reported 5-HTTLPR×Environment interaction was followed by a number of replications, several large studies, however, showed inconsistent results. We found that this discrepancy in results could partly be explained by the different sex and age composition of different samples. For example, the S/S genotype might increase an individual’s susceptibility to depression under stressful conditions only in females, not in males. Data based on adolescent and elderly samples often led to negative results. We then discussed the mechanisms underlying 5-HTTLPR×Stress interaction on depression. First, in neuroimaging studies, S allele was found to influence the activity of amygdala, a brain region being central to the neural circuitry mediating emotional arousal and vigilance across species. S allele carriers exhibited greater amygdala activity than L allele homozygotes. Studies also found that the gray matter volume in a specific region of the PFC, the perigenual anterior cingulate cortex （pACC）, was significantly reduced in S allele carriers as compared with L allele homozygotes. Moreover, fMRI analysis of relative activation of the pACC and amygdala during presentation of angry and fearful faces revealed a relatively weaker functional coupling between these regions in the S allele carriers. These findings suggested that 5-HTTLPR might influence the emotion-processing brain region and circuits, thus, rendering the liability to depression. Second, findings from psychophysiological studies suggested that another possible mechanism involved the hyperactivity of the hypothalamic-pituitary-adrenal （HPA） axis in response to stress for S/S carriers. When confronted with stressful life events, individuals with S/S genotype might be at a greater risk for depression due to heightened cortisol exposure. There were also situtations in which the 5-HTTLPR×Environment interaction was further subjected to the influence of other genes. We then speculated the possibility of epistatic effects and Gene×Gene×Environment interactions. CYP2C9 gene and BDNF gene emerged as two candidates for epistasis effects with 5-HTTLPR. Individuals carrying both S and CYP2CY＊3 alleles were found to be at a greater risk of suffering depression. Studies also found significant a three-way interaction between 5-HTTLPR, BDNF, and childhood maltreatment in predicting the risk of depression. Finally, future directions were suggested. We anticipated the combination of research approach of genetics, animal models, neruoimaging and neuroendorinology to explore the more detailed mechanisms underlying 5-HTTLPR×Stress interaction in depression.