Department of Psychology, Georgetown University, 306 White-Gravenor, Washington, DC 20057, United States.
Department of Psychology, Georgetown University, 306 White-Gravenor, Washington, DC 20057, United States; Children's Research Institute, Children's National Medical Center, Washington, DC, United States.
Psychiatry Res Neuroimaging. 2019 Mar 30;285:1-8. doi: 10.1016/j.pscychresns.2019.01.010. Epub 2019 Jan 29.
The serotonin transporter (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) gene polymorphisms have been associated with risk for affective disorders and functional variability of the amygdala. We examined whether the two genotypes interactively influence intrinsic functional connectivity (FC) of the amygdala and whether FC mediates the genetic association with anxiety. Eighty genotyped healthy adults underwent resting state fMRI and completed the self-reported State-Trait Anxiety Inventory. Interactive genetic association with anxiety was observed such that effects of 5-HTTLPR depended on the BDNF Val66Met polymorphism (rs6265 variant), with higher anxiety scores in short and Met carriers compared to the other allelic groups. Voxel-wise FC with left and right amygdala seeds identified regions that were sensitive to variability in anxiety scores. A significant moderated mediation model demonstrated that the effect of 5-HTTLPR genotype on anxiety, moderated by BDNF Val66Met genotype, was fully mediated by FC between the left amygdala and the right dorsolateral prefrontal cortex, a cognitive control-related region, during a task-free state. FC was highest in carriers of the 5-HTTLPR short allele and BDNF Met allele. These findings establish intrinsic amygdala-prefrontal functional connectivity as a potential intermediate phenotype for anxiety, an important step toward identification of causal pathways for vulnerability to affective disorders.
血清素转运体（5-HTTLPR）和脑源性神经营养因子（BDNF）基因多态性与情感障碍的风险和杏仁核的功能变异性有关。我们研究了这两种基因型是否相互影响杏仁核的内在功能连接（FC），以及 FC 是否介导与焦虑相关的遗传关联。80 名基因分型的健康成年人接受了静息状态 fMRI 检查，并完成了状态-特质焦虑量表的自我报告。观察到与焦虑的交互遗传关联，即 5-HTTLPR 的作用取决于 BDNF Val66Met 多态性（rs6265 变体），与其他等位基因组相比，短型和 Met 携带者的焦虑评分更高。左、右杏仁核种子的体素水平 FC 确定了对焦虑评分变化敏感的区域。一个显著的调节中介模型表明，5-HTTLPR 基因型对焦虑的影响，受 BDNF Val66Met 基因型调节，完全由左杏仁核和右背外侧前额叶皮层（与认知控制相关的区域）之间的 FC 介导，在无任务状态下。5-HTTLPR 短等位基因和 BDNF Met 等位基因携带者的 FC 最高。这些发现确立了内在杏仁核-前额叶功能连接作为焦虑的潜在中间表型，这是确定易感性情感障碍的因果途径的重要一步。
