遗传风险基因PCDH17参与心境障碍发病的机制研究

Major mood disorders primarily include major depressive disorder and bipolar disorder. We previously characterized that the gene Protocadherin 17 (PCDH17) was a mood disorder susceptible gene in Europeans, and its mRNA expression was significantly associated with the onset of the disease as well as pathological disruption of cognition, mood stability，amygdala structure and function. We also found that overexpression of PCDH17 led to changes in the density and morphology of dendritic spines in mouse neurons (Molecular Psychiatry, 2017). However, the role of PCDH17 in the genetic risk and pathogenesis of mood disorders in Chinese remains to be elucidated. We therefore propose to analyze the association between PCDH17 and genetic susceptibility of mood disorders in Chinese, followed by studies using mice with conditional knock-in of this gene to understand its resultant malfunction and/or alterations in cognitive ability, mood, and cellular physiology of neurons. In addition, our recent unpublished findings also indicate potential interaction between PCDH17 and the anti-depressant Vortioxetine. We thus will delve into the role of PCDH17 in the anti-depressive effects of Vortioxetine using murine and cellular models. These studies will provide hints on the molecular mechanisms underlying the susceptibility of mood disorders conferred by PCDH17.

心境障碍主要包括抑郁症和双相情感障碍等。我们前期发现原钙黏蛋白17（PCDH17）在欧洲人群是一个心境障碍易感基因，其表达量升高与疾病的发病风险及伴随的病理变化（认知能力、情绪控制、杏仁核结构和功能等）显著相关，且该基因过表达会导致树突棘密度及形态改变（发表于《Molecular Psychiatry》）。然而，PCDH17在中国心境障碍人群中的遗传机理和病理机制仍未知。在本项目中，我们拟分析PCDH17在中国心境障碍人群中的遗传风险，并利用条件性敲入小鼠研究PCDH17可否引起认知、情绪等行为异常和神经元表型变化，进而探索其分子机制。此外，基于抗抑郁药物Vortioxetine影响PCDH17表达的预实验结果，我们将通过小鼠和细胞模型深入了解PCDH17是否参与该药物改善抑郁症状的作用，并解析其分子机理。本研究有助于理解PCDH17在心境障碍发生中的生物学功能。

心境障碍主要包括抑郁症和双相情感障碍，严重危害人类健康。2018年我们发表于Molecular Psychiatry杂志的研究成果发现PCDH17（原钙黏蛋白17）在欧洲人群是一个心境障碍易感基因，其表达量升高与疾病的发病风险及伴随的病理变化（认知能力、情绪控制、杏仁核结构和功能等）显著相关，且该基因过表达会导致树突棘密度及形态改变，但是该基因中国心境障碍人群中的遗传机理及致病机制仍未知。本项目周期为2018年至2022年，在执行期内，我们首先在中国人群双相情感障碍的样本中（1,007个病例与2,242健康对照），通过遗传学分析，独立验证发现rs9537793与双相情感障碍的发生风险具有显著相关性（优势比=0.8384，P值=0.001494）；此外，我们还应用基于生物素共价修饰的空间邻近标记及免疫功沉淀方法，鉴定出另一个重要风险基因SETD1A可与PCDH17直接相互作用，提示精神疾病风险基因之间的复杂互作性；然而，我们构建过表达人源PCDH17敲入小鼠模型，未能按照预期过表达PCDH17，因此，我们通过腺病毒载体系统结合立体显微注射技术，在小鼠腹侧海马过表达鼠源PCDH17并进行一系列小鼠行为学范式分析，结果并未发现该基因表达改变会导致小鼠模型行为异常，我们分析认为，可能是我们注射的小鼠特定脑区未能体现PCDH17的生物学功能。通过本项目的开展，我们不仅进一步理解了PCDH17在中国人群心境障碍患者中的致病风险，也首次鉴定到PCDH17与SETD1A基因之间的直接相互作用，促进我们对心境障碍致病机制的系统理解。