The genome-wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response.
The genome-wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response.
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DOI：
10.1002/ajmg.b.32532
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Breen G
中科院分区：
文献类型：
--
作者：
Powell TR;Murphy T;de Jong S;Lee SH;Tansey KE;Hodgson K;Uher R;Price J;Thuret S;Breen G
抗抑郁药诱导的海马神经发生（AHN）被假设为有助于长期治疗后重度抑郁症患者海马体积的增加。此外，啮齿动物研究表明AHN可能是介导抗抑郁药治疗益处的细胞机制。在这里，我们进行了人类细胞中与AHN相关的全基因组表达变化的第一次调查。我们确定了在AHN过程中显著激活的基因表达网络，并进行了基因集分析，以探讨AHN、海马体积和抗抑郁反应之间的分子关系。后者是使用从30，717名个体收集的全基因组关联汇总数据作为ENIGMA联盟的一部分（海马体积数据集的遗传预测因子），以及从1，222名重度抑郁症患者收集的数据作为NEWMEDS项目的一部分（抗抑郁药反应的遗传预测因子数据集）。我们的研究结果表明，选择性5-羟色胺再摄取抑制剂艾司西酞普兰在人体细胞中诱发AHN;剂量依赖性地增加细胞向成神经细胞的分化，以及增加胶质细胞生成。激活的全基因组表达网络与轴突和微管形成以及核糖体生物发生有关。基因集分析显示，与AHN相关的基因表达变化在名义上富集了预测海马体积的基因，但没有预测治疗反应的基因。
Antidepressant‐induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long‐term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome‐wide expression changes associated with AHN in human cells. We identify gene expression networks significantly activated during AHN, and we perform gene set analyses to probe the molecular relationship between AHN, hippocampal volume, and antidepressant response. The latter were achieved using genome‐wide association summary data collected from 30,717 individuals as part of the ENIGMA Consortium (genetic predictors of hippocampal volume dataset), and data collected from 1,222 major depressed patients as part of the NEWMEDS Project (genetic predictors of response to antidepressants dataset). Our results showed that the selective serotonin reuptake inhibitor, escitalopram evoked AHN in human cells; dose‐dependently increasing the differentiation of cells into neuroblasts, as well as increasing gliogenesis. Activated genome‐wide expression networks relate to axon and microtubule formation, and ribosomal biogenesis. Gene set analysis revealed that gene expression changes associated with AHN were nominally enriched for genes predictive of hippocampal volume, but not for genes predictive of therapeutic response.