Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Biol Psychiatry. 2011 Mar 15;69(6):513-9. doi: 10.1016/j.biopsych.2010.09.024. Epub 2010 Nov 2.
Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for depression in interaction with psychosocial adversity across the life span. However, genetically driven deficient serotonin transporter (5-HTT) function would not have been maintained throughout evolution if it only exerted negative effects without conveying any gain of function. Here, we review recent findings that humans and nonhuman primates carrying the s variant of the 5-HTTLPR outperform subjects carrying the long allele in an array of cognitive tasks and show increased social conformity. In addition, studies in 5-HTT knockout rodents are included that provide complementary insights in the beneficial effects of the 5-HTTLPR s-allele. We postulate that hypervigilance, mediated by hyperactivity in corticolimbic structures, may be the common denominator in the anxiety-related traits and (social) cognitive superiority of s-allele carriers and that environmental conditions determine whether a response will turn out to be negative (emotional) or positive (cognitive, in conformity with the social group). Taken together, these findings urge for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR variants. In fact, these factors may counterbalance or completely offset the negative consequences of the anxiety-related traits. This notion may not only explain the modest effect size of the 5-HTTLPR and inconsistent reports but may also lead to a more refined appreciation of allelic variation in 5-HTT function.
越来越多的证据表明，人类 5-羟色胺转运体基因（5-HTT，SERT，SLC6A4）中的重复长度多态性短（s）、低表达变体与焦虑相关特征以及与整个生命周期的心理社会逆境相互作用的抑郁风险增加有关。然而，如果仅仅产生负面影响而没有任何功能增益，那么由基因驱动的 5-羟色胺转运体（5-HTT）功能缺陷就不会在整个进化过程中得到维持。在这里，我们回顾了最近的发现，携带 5-HTTLPRs 短等位基因的人类和非人类灵长类动物在一系列认知任务中表现优于携带长等位基因的个体，并且表现出更高的社会从众性。此外，还包括 5-HTT 敲除啮齿动物的研究，这些研究为 5-HTTLPRs 短等位基因的有益作用提供了补充见解。我们假设，由皮质边缘结构的过度活跃介导的过度警惕可能是与焦虑相关特征和（社会）认知优势的携带者的共同特征，而环境条件决定了反应是负面的（情绪）还是正面的（与社会群体一致的认知）。综上所述，这些发现促使人们对当前以缺陷为导向的 5-HTTLPR 变体的概念进行改变。事实上，这些因素可能会抵消或完全抵消与焦虑相关特征的负面后果。这个概念不仅可以解释 5-HTTLPR 的适度效应大小和不一致的报告，还可以导致对 5-HTT 功能等位基因变异的更精细的理解。
