Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment.
Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment.
复制标题
抑郁症基因组风险对遗忘性轻度认知障碍转化影响的神经生物学底物。
作者：
Xu Jiayuan;Li Qiaojun;Qin Wen;Jun Li Mulin;Zhuo Chuanjun;Liu Huaigui;Liu Feng;Wang Junping;Schumann Gunter;Yu Chunshui
抑郁症增加了从遗忘性轻度认知障碍到阿尔茨海默病的转换风险，其机制尚不清楚。我们假设，重度抑郁症的累积基因组风险可能是转换风险增加的候选原因。本研究旨在探讨重度抑郁症特异性遗传变异（PRSsMDD）多基因风险评分对非抑郁性遗忘性轻度认知障碍向阿尔茨海默病转化的预测作用及其潜在的神经生物学机制。prssmdd可以预测遗忘型轻度认知障碍向阿尔茨海默病的转化，高危评分的遗忘型轻度认知障碍患者的转化率比低危评分的遗忘型轻度认知障碍患者高16.25%。prssmdd与左海马体积相关，介导了prssmdd对遗忘性轻度认知障碍转化的预测作用。通过不同的策略将抑郁症特异性基因变异定位到基因中，并通过富集分析和蛋白-蛋白相互作用网络分析发现这些基因参与了发育过程和淀粉样蛋白- β结合。它们在胎儿发育中后期的海马体中表现出时间特异性表达。这些基因的细胞类型特异性表达分析表明，在海马锥体神经元和中间神经元中有显著的过度表达。这些跨尺度的神经生物学分析和功能注释表明，抑郁症特异性的主要遗传变异可能通过调节早期海马发育和淀粉样蛋白结合，增加从遗忘性轻度认知障碍到阿尔茨海默病的转化。prssmdd可以作为一种补充措施，选择遗忘性轻度认知障碍患者，并具有高阿尔茨海默病的转化风险。
Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer’s disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer’s disease, and its underlying neurobiological mechanisms. The PRSsMDDcould predict the conversion from amnestic mild cognitive impairment to Alzheimer’s disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDDwas correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDDon the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein–protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer’s disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDDcould be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer’s disease.