SLC6A4基因与环境因素交互作用对厌食症反应抑制环路影响的纵向研究

Anorexia Nervosa (AN) is a chronic refractory mental disorder commonly with highest mortality. Patients with AN often start with restricting subtype (AN-R), and most of them could develop into bingeing/purging subtype, which is more serious than AN-R with worse prognosis. The applicant’s preliminary studies found that the genetics and environmental factors played an important role in AN，e.g .the SLC6A4 gene is a susceptibility gene, the characteristic of the promoter of the SLC6A4 gene is hypermethylation, there is low intimacy and high conflict in the family environment etc.; but the concrete pathological mechanism need to be studied further. Both the international research and our previous studies in brain imaging found that the response inhibition circuit related brain regions showed abnormal function in patients with AN. Based on the above and the latest international progress, this study proposes the hypothesis that the interaction of the SLC6A4 gene and environmental factors could affect the function of brain response inhibition circuit, resulting in the occurrence and development of AN. We would recruit the first onset untreated female AN-R patients, adopting a longitudinal research design. Baseline and 12 months follow-up measurements include the detection of the SNP and DNA methylation of the promoter of the SLC6A4 gene, psychological assessments of the risk environmental factors, e.g. family environment, adverse life events, etc., the brain imaging scanning of the response inhibition circuit, etc. We would explore the effect of the interaction between gene and environment on brain response inhibition circuit from the perspective of imaging genetics, to illustrate the pathomechanism of AN and its two subtypes, identify susceptible factors and biological markers of AN, and provide scientific basis for early diagnosis and early intervention such as family intervention.

厌食症（AN）是我国近年来快速增长、死亡率最高的慢性难治性精神障碍，常以限制型起病，多数发展为暴食/清除型而致预后更差。遗传和环境因素在AN发生发展中起重要作用，但具体机制不明。申请人前期研究发现：SLC6A4基因为AN易感基因且启动子区呈高甲基化状态，家庭环境特点为低亲密度、低情感表达，脑影像研究显示反应抑制脑区异常。结合国内外最新进展提出本研究假说：SLC6A4基因和环境因素交互作用通过影响脑反应抑制环路而致AN发生发展。本项目将采用纵向研究设计，以首发未治疗女性限制型AN患者为研究对象，通过检测SLC6A4基因启动子区多态和甲基化水平、评估环境因素（家庭环境等）、进行MRI扫描等并进行12个月随访，从影像遗传学角度探索基因环境交互作用对AN反应抑制环路及临床转归的影响，以阐明AN及其亚型的病理机制，找出早期诊断分型、预测临床转归的生物学标记，并为AN早期干预（家庭干预）提供理论依据。

神经性厌食（Anorexia Nervosa， AN），即厌食症，是以怕胖、盲目减肥、消瘦、闭经等为特征的一类慢性难治性精神障碍，本项目旨在分析国内外现状及发展动态的基础上，开展AN抑制控制功能的病理机制研究，以进一步阐明 AN 发生发展的机制。本研究使用经典的信号停止任务（SSRT）检查AN患者的抑制控制功能，发现不管在何种难度水平下，AN患者脑电的P300幅值均减弱，N2潜伏期均延长。同时AN患者N2潜伏期在任务难度降低时延长，而健康对照（HC）则没有发现此现象。磁共振研究发现，AN-R虽然过度控制饮食，但其神经激活程度不高，可能是抑制控制环路的效率提高和易化导致，使得控制过程进一步易化。结构影像学研究显示，AN患者的尾状核体积增大，楔前叶皮层厚度降低。提示AN患者抑制控制功能损害的潜在脑机制。此外，AN患者也存在血生化指标的异常，研究发现其血清asprosin水平相比HC更高，且与病程和病理心理水平有关。在AN患者的病理心理学机制研究上，本项目通过问卷研究发现应激事件可以通过诱导抑郁情绪，从而诱发对自身形象的不满意，加重患者的疾病严重程度。为了评估家庭因素对AN患者疾病的影响，本项目调查了自评家庭负担量表在AN患者家庭中的信效度水平。确定了其在AN患者家庭中使用的可行性。基于本项目，负责人构建了AN患者的长期随访队列，共追踪限制型神经性厌食（AN-R）患者113人，其中13人在12个月随访时转化为暴食-清除型神经性厌食（AN-BP），转化率为11.5%。本项目建立了较大规模的AN队列，并探索了AN患者核心症状异常的神经机制，为后续AN的优化治疗提供了重要依据。