Hariri Ahmad R, Drabant Emily M, Munoz Karen E, Kolachana Bhaskar S, Mattay Venkata S, Egan Michael F, Weinberger Daniel R
Genes, Cognition and Psychosis Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892, USA.
Arch Gen Psychiatry. 2005 Feb;62(2):146-52. doi: 10.1001/archpsyc.62.2.146.
A common regulatory variant (5-HTTLPR) in the human serotonin transporter gene (SLC6A4), resulting in altered transcription and transporter availability, has been associated with vulnerability for affective disorders, including anxiety and depression. A recent functional magnetic resonance imaging study suggested that this association may be mediated by 5-HTTLPR effects on the response bias of the human amygdala-a brain region critical for emotional and social behavior-to environmental threat.
To examine the effects of 5-HTTLPR genotype on the reactivity of the human amygdala to salient environmental cues with functional magnetic resonance imaging in a large (N = 92) cohort of volunteers carefully screened for past and present medical or psychiatric illness, and to explore the effects of 5-HTTLPR genotype as well as amygdala reactivity on harm avoidance, a putative personality measure related to trait anxiety.
We now confirm the finding of 5-HTTLPR short allele-driven amygdala hyperreactivity in a large independent cohort of healthy subjects with no history of psychiatric illness or treatment. Furthermore, we demonstrate that these genotype effects on amygdala function are consistent with a dominant short allele effect and are equally prominent in men and women. However, neither 5-HTTLPR genotype, amygdala reactivity, nor genotype-driven variability in this reactivity was reflected in harm avoidance scores.
Our results reveal a potent modulatory effect of the 5-HTTLPR on amygdala reactivity to environmental threat. Since this genetically driven effect exists in healthy subjects, it does not, in and of itself, predict dimensions of mood or temperament. As such, the 5-HTTLPR may represent a classic susceptibility factor for affective disorders by biasing the functional reactivity of the human amygdala in the context of stressful life experiences and/or deficient cortical regulatory input.
人类血清素转运体基因（SLC6A4）中的一种常见调控变异（5-羟色胺转运体基因连锁多态性区域，5-HTTLPR）会导致转录改变和转运体可用性变化，它与包括焦虑和抑郁在内的情感障碍易感性有关。最近一项功能磁共振成像研究表明，这种关联可能是由5-HTTLPR对人类杏仁核（对情绪和社会行为至关重要的脑区）对环境威胁的反应偏差的影响所介导的。
在一大群（N = 92）经过仔细筛查以排除既往和当前医学或精神疾病的志愿者中，通过功能磁共振成像检查5-HTTLPR基因型对人类杏仁核对显著环境线索的反应性的影响，并探讨5-HTTLPR基因型以及杏仁核反应性对回避伤害（一种与特质焦虑相关的假定人格测量指标）的影响。
我们现在在一个没有精神疾病病史或治疗史的大型独立健康受试者队列中证实了5-HTTLPR短等位基因驱动的杏仁核高反应性这一发现。此外，我们证明这些基因型对杏仁核功能的影响与显性短等位基因效应一致，并且在男性和女性中同样显著。然而，5-HTTLPR基因型、杏仁核反应性或这种反应性中由基因型驱动的变异性均未在回避伤害得分中体现出来。
我们的结果揭示了5-HTTLPR对杏仁核对环境威胁的反应性具有强大的调节作用。由于这种由基因驱动的效应存在于健康受试者中，其本身并不能预测情绪或气质维度。因此，5-HTTLPR可能通过在应激性生活经历和/或皮质调节输入不足的情况下使人类杏仁核的功能反应性产生偏差，从而代表情感障碍的一种经典易感性因素。
