心境障碍家系易感基因MAPKAP1的遗传机制研究

Mood disorder is a group of serious, complex mental illnesses. Although their etiology remains largely unknown, a lot of studies have shown that mood disorders have a strong genetic component with heritabilities estimated to be as high as 80%-85%.Despite of the success of genome-wide association studies, the identified and validated causal or associated genetic variants so far can explain only a small portion of the heritability. Possible reasons for the missing inheritance include genetic heterogeneity, rare variants, genetic-environment interaction. Our research group has recently conducted a whole exome sequecing studying of a pedigree enriched for mood disorders and identified 26 candidate rare variants using tools of bioinformatics and genetic epidemiology. The top-ranked variant is located in the intronic region of the MAPKAP1 gene, a key component of mTORC2 signaling complex necessary for AKT phosphorylation. Our team have previously reported that the key genes, AKT1 and GSK3B, of mTORC2 signaling appear to be associated with MDD in the Han Chinese population. We hypothesize that MAPKAP1 play an important role in the development of mood disorders through proliferation, differentiation and apoptosis of neurons. We therefore propose to conduct a comprehensive study, including in vitro, in vivo, and population-based research, to explore the functional role of MAPKAP1 gene in neuronal plasticity and the possible mechanisms how the identified mutations are related to mood disorders. We will be particularly focused on elucidating the impact of the identified mutations on protein structure and function and/or expression levels of the corresponding transcripts. We expect that our study will advance the understanding of mood disorder and provide new insight into their pathogenesis, early diagnosis and treatment and prevention.

心境障碍是一类危害性极大的复杂性疾病，探明其病理机制意义重大，遗传学研究显示其遗传度高达80%-85%。虽然已有大量心境障碍遗传学研究，仍没有明确定论，究其原因可能与心境障碍为复杂性疾病及研究方法有关。课题组前期选择遗传变异相对小、同质性相对好的心境障碍家系样本，采用全基因组外显子测序技术，筛选出心境障碍家系易感基因丝裂原活化蛋白激酶相关蛋白（MAPKAP1）。该基因通过雷帕霉素靶蛋白信号通路（PI3K/Akt/mTOR）发挥神经可塑性功能，结合既往心境障碍神经可塑性假说及课题组对通路中相关基因的阳性研究成果，我们推测：MAPKAP1参与神经元增殖、分化和凋亡而影响心境障碍的发生、发展。本项目将采用细胞、动物水平功能学实验及临床研究相结合的研究设计，从多层面、多角度系统探讨MAPKAP1是否影响心境障碍及可塑性功能，为进一步阐明心境障碍病理生理机制提供新的理论。

心境障碍是一类危害性极大的复杂性疾病，探明其病理机制意义重大，遗传学研究显示其遗传度高达80%-85%。课题组前期选择遗传变异相对小、同质性相对好的心境障碍家系样本，采用全基因组外显子测序技术，筛选出心境障碍家系易感基因丝裂原活化蛋白激酶相关蛋白（MAPKAP1）。该基因通过雷帕霉素靶蛋白信号通路（PI3K/Akt/mTOR）发挥神经可塑性功能，结合既往心境障碍神经可塑性假说及课题组对通路中相关基因的阳性研究成果，推测MAPKAP1参与神经元增殖、分化和凋亡而影响心境障碍的发生发展。进一步进行人群频率及表达水平验证，并采用细胞、动物水平/人群水平功能学实验，从多层面、多角度系统探讨MAPKAP1介导的神经可塑性在心境障碍发生、发展中的作用。人群频率验证显示rs78809014等位基因G突变频率为6.1%，明显高于CHB+CHS3.1%，携带有G等位基因的患者认知障碍因子、有罪感及自杀分值明显高于携带有C等位基因者。MAPKAP1的RNA表达水平在病例组明显高于对照组，经过8周抗抑郁药物治疗，MAPKAP1表达水平明显减低。体内体外验证均提示MAPKAP1表达降低可引起通路相关基因表达发生变化。提示MAPKAP1基因可能是心境障碍的易感基因，通过（PI3K/Akt/mTORC2）通路发挥其神经可塑性生物学功能参与心境障碍的发生、发展。