During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

在发育过程中，遗传和环境因素相互作用以改变特定的表型。在人类和动物模型中，早期逆境都会影响认知灵活性，这是一种与行为适应环境变化有关的重要大脑功能。认知功能异常与前额叶皮层 (PFC) 突触连接的变化和突触蛋白水平的改变有关。我们调查了在前额叶皮层中与突触蛋白 VAMP1 共表达的基因网络表达的个体差异是否会调节早期环境质量对儿童在认知灵活性任务中表现的影响。选择在儿童早期过表达并与 PFC 中的 VAMP1 基因共表达的基因进行研究。来自这些基因的 SNP（聚集后）被编译成基于表达的多基因评分（PFC-ePRS-VAMP1）。我们使用类似的认知灵活性任务评估了两个队列中 4 岁儿童的认知表现。在第一个队列 (MAVAN) 中，我们使用了两个 CANTAB 任务：(a) 内/外维集移位 (IED) 任务，和 (b) 空间工作记忆 (SWM) 任务。在第二个队列 GUSTO 中，我们使用了维度变化卡片分类 (DCCS) 任务。结果表明，在 4 岁儿童中，PFC-ePRS-VAMP1 网络调节了对早期逆境对注意力灵活性测试表现的影响的反应。对于空间工作记忆任务，观察到了相同的结果。与注意力灵活性相比，逆向学习显示出环境的相反影响，由 ePRS 调节。进行了并行 ICA 分析，以确定基于全脑体素的灰质密度与构成 PFC-ePRS-VAMP1 的 SNP 之间的关系。早期环境预测了前额叶和颞叶皮质等区域灰质含量的差异，这与与 Wnt 信号通路相关的遗传成分显着相关。我们的数据表明，PFC 中与 VAMP1 共表达的基因网络调节了早期环境对儿童认知功能的影响。与 Wnt 信号通路相关的遗传成分显着相关。我们的数据表明，PFC 中与 VAMP1 共表达的基因网络调节了早期环境对儿童认知功能的影响。与 Wnt 信号通路相关的遗传成分显着相关。我们的数据表明，PFC 中与 VAMP1 共表达的基因网络调节了早期环境对儿童认知功能的影响。