基于“基因-脑-行为”框架探讨nNOS/NO通路关键基因NOS1在ADHD发病机制中的作用

Attention-Deficit/Hyperactivity Disorder (ADHD) is considered as a neurodevelopmental disorder with high heritability of about 0.76. Neuronal nitric oxide synthase (nNOS) -derived nitric oxide (NO) has been regarded as a nonsynaptic extension of glutamate, could regulate the function of monoaminergic systems and influence neurodevelopment. The key gene of nNOS/NO pathway, NOS1, may be associated with ADHD, especially with its impulsivity and aggressive behavior. However, more work is needed to illustrate its precise genetic effect model and the underlying brain mechanism. In the present study, we plan to detect the genotype of NOS1 and the up-/downstream genes for 2000 ADHD children and 1000 normal control children. By systematic genetic analyses, including SNP-based, gene-gene interaction and analyses of the accumulative effects of multiple loci, we anticipate exploring the association of NOS1 with ADHD and its cognitive/behavioral abnormity (including impulsivity, inhibition deficit and aggression), and illustrating its genetic effect model. Furthermore, with the associated genetic risk factors as prior information, we will use the strategy of multimodal fusion with reference to guide the fusion of multimodal imaging data of prefrontal cortex, including brain structure, brain function and cerebral blood flow. This could help us to identify the imaging features closely related to the genetic risk factors. We anticipate constructing the gene-brain-behavior model for NOS1 in the pathogenesis of ADHD and enrolling nNOS/NO pathway dysfunction into the genetic susceptibility map of ADHD, which will supply possible biomarkers for ADHD diagnosis.

注意缺陷多动障碍（ADHD）是一种神经发育障碍性疾病，遗传度约为0.76。神经元型一氧化氮合酶（nNOS）来源的一氧化氮（NO）是谷氨酸的非突触性延伸，调节单胺系统功能，影响神经发育；nNOS/NO通路关键基因NOS1与ADHD及其冲动、攻击性等存在关联，但其作用模式及脑机制尚需阐明。本研究拟纳入2000例ADHD儿童及1000名正常对照儿童，检测NOS1及通路上下游基因，通过单位点、基因-基因交互作用、多位点集聚效应等系统性遗传分析，探讨NOS1与ADHD及其认知行为异常（冲动/抑制缺陷、攻击性）的关联，阐释其遗传作用模式；进一步采用有监督的多模态融合分析，以关联的遗传变异作为先验信息，引导前额叶脑结构、脑功能、脑血流数据的融合，探索遗传相关的脑影像指征。以期构建NOS1参与ADHD发病的基因-脑-行为模型，将nNOS/NO通路功能失调纳入ADHD病因学图谱，为其诊断提供可能的生物标记。

注意缺陷多动障碍（ADHD）是最常见的神经发育障碍性疾病之一，其遗传度约为0.76，说明遗传因素在其发病机制中发挥重要作用。本项目关注nNOS/NO通路及其关键基因NOS1，以多模态脑影像融合指标作为“桥梁”，构建“基因-脑-行为”路径，系统深入地探讨NOS1基因在ADHD发生发展过程中发挥作用的脑神经机制。研究发现NOS1基因遗传变异及其与NO信号通路相关基因交互作用主要与ADHD多动/冲动症状、情绪失调、抑制缺陷等重要临床特征及认知功能损害存在关联；NOS1基因遗传多态可能通过影响抑制网络和默认网络脑区的重要融合特征参与ADHD核心认知缺陷“抑制功能”的病理机制，可能通过影响情绪关键脑区杏仁核亚区与右侧扣带回的功能连接参与ADHD情绪失调的发生发展。此外，新的遗传易感基因及遗传作用模式的探索、多模态脑影像数据的深入挖掘、临床表型特征的新模式分析也为“基因-脑-行为”模型的探讨和构建进一步提供了多维度数据的关键指标。本项目研究结果能够帮助我们发现经典神经递质通路上游的相关遗传易感因素，更好地阐释ADHD的高遗传度，全面描绘ADHD的遗传易感图谱；同时，有望为未来ADHD新药开发提供一定的理论依据，为疾病转归提供客观生物标记，遗传易感因素相关的脑结构/功能异常指征的确定有望在未来为临床干预提供潜在的靶点。