Wurtman Richard J
Department of Brain and Cognitive Sciences, and Clinical Research Center, Massachusetts Institute of Technology, Cambridge 02139, USA.
Metabolism. 2005 May;54(5 Suppl 1):16-9. doi: 10.1016/j.metabol.2005.01.007.
A relationship between genetic makeup and susceptibility to major depressive disorder (MDD) has long been suspected on the basis of family and twin studies. A metaanalysis of reports on the basis of twin studies has estimated MDD's degree of heritability to be 0.33 (confidence interval, 0.26-0.39). Among families exhibiting an increased prevalence of MDD, risk of developing the illness was enhanced in members exposed to a highly stressful environment. Aberrant genes can predispose to depression in a number of ways, for example, by diminishing production of growth factors that act during brain development. An aberrant gene could also increase or decrease a neurotransmitter's release into synapses, its actions, or its duration of activity. The gene products of greatest interest at present are those involved in the synthesis and actions of serotonin; among them, the serotonin-uptake protein localized within the terminals and dendrites of serotonin-releasing neurons. It has been found that the Vmax of platelet serotonin uptake is low in some patients with MDD; also, Vmax is highly correlated in twins. Antidepressant drugs such as the selective serotonin reuptake inhibitors act on this uptake protein. The specific genetic locus causing serotonin uptake to be lower in some patients with major depression involves a polymorphic region (5-HTTLPR) in the promoter region of the gene for the uptake protein. The gene itself exists as several alleles, the short "S" allele and the long "L" allele. The S variant is associated with less, and the L variant with more, of the uptake protein. The effect of stressful life events on depressive symptoms in young adults was found to be significantly stronger among SS or SL subjects than among LL subjects. Neuroimaging studies showed that people with the SS or SL alleles exhibited a greater activation of the amygdala in response to fearful stimuli than those with LL. It has been reported recently that mutations in the gene that controls serotonin synthesis in the human brain (tryptophan hydroxylase) also predispose to mood disturbances. It may be asked whether people who lack a psychiatric history should be advised to avoid stressful environments if they are found to carry the SS or SL alleles.
基于家族研究和双胞胎研究，长期以来人们一直怀疑基因构成与重度抑郁症（MDD）易感性之间存在关联。一项基于双胞胎研究报告的荟萃分析估计，MDD的遗传度为0.33（置信区间为0.26 - 0.39）。在MDD患病率增加的家族中，暴露于高压力环境的成员患该病的风险会增加。异常基因可通过多种方式使人易患抑郁症，例如，减少在大脑发育过程中起作用的生长因子的产生。异常基因还可能增加或减少神经递质释放到突触中的量、其作用或其活性持续时间。目前最受关注的基因产物是那些参与血清素合成和作用的产物；其中，血清素摄取蛋白定位于血清素释放神经元的终末和树突内。研究发现，一些MDD患者血小板血清素摄取的最大速率（Vmax）较低；此外，双胞胎之间的Vmax高度相关。选择性血清素再摄取抑制剂等抗抑郁药物作用于这种摄取蛋白。导致一些重度抑郁症患者血清素摄取较低的特定基因位点涉及摄取蛋白基因启动子区域的一个多态性区域（5-HTTLPR）。该基因本身以几种等位基因形式存在，即短的“S”等位基因和长的“L”等位基因。S变体与较少的摄取蛋白相关，L变体与较多的摄取蛋白相关。研究发现，在年轻成年人中，应激性生活事件对抑郁症状的影响在携带SS或SL等位基因的个体中比在携带LL等位基因的个体中显著更强。神经影像学研究表明，携带SS或SL等位基因的人在面对恐惧刺激时杏仁核的激活程度比携带LL等位基因的人更高。最近有报道称，控制人脑血清素合成的基因（色氨酸羟化酶）发生突变也会使人易患情绪障碍。可能会有人问，如果发现没有精神病史的人携带SS或SL等位基因，是否应该建议他们避免压力环境。
