Department of Radiology and Imaging Sciences, and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Neurology, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam, Republic of Korea.
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Neurobiol Aging. 2020 Apr;88:24-32. doi: 10.1016/j.neurobiolaging.2019.12.001. Epub 2019 Dec 10.
Transcriptomics has become an important tool for identification of biological pathways dysregulated in Alzheimer's disease (AD). We performed a network-based gene expression analysis of blood-based microarray gene expression profiles using 2 independent cohorts, Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 661) and AddNeuroMed (N = 674). Weighted gene coexpression network analysis identified 17 modules from ADNI and 13 from AddNeuroMed. Four of the modules derived in ADNI were significantly related to AD; 5 modules in AddNeuroMed were significant. Gene-set enrichment analysis of the AD-related modules identified and replicated 3 biological pathways including the Fc gamma receptor-mediated phagocytosis pathway. Module-based association analysis showed the AD-related module, which has the 3 pathways, to be associated with cognitive function and neuroimaging biomarkers. Gene-based association analysis identified PRKCD in the Fc gamma receptor-mediated phagocytosis pathway as being significantly associated with cognitive function and cerebrospinal fluid biomarkers. The identification of the Fc gamma receptor-mediated phagocytosis pathway implicates the peripheral innate immune system in the pathophysiology of AD. PRKCD is known to be related to neurodegeneration induced by amyloid-β.
转录组学已成为鉴定阿尔茨海默病（AD）中失调的生物途径的重要工具。我们使用两个独立的队列，阿尔茨海默病神经影像学倡议（ADNI；N=661）和 AddNeuroMed（N=674），对基于血液的微阵列基因表达谱进行了基于网络的基因表达分析。加权基因共表达网络分析从 ADNI 中鉴定出 17 个模块，从 AddNeuroMed 中鉴定出 13 个模块。ADNI 中得出的 4 个模块与 AD 显著相关；AddNeuroMed 中有 5 个模块是显著的。AD 相关模块的基因集富集分析确定并复制了包括 Fc 受体介导的吞噬途径在内的 3 个生物学途径。基于模块的关联分析显示，具有 3 条途径的 AD 相关模块与认知功能和神经影像学生物标志物相关。基于基因的关联分析确定了 Fc 受体介导的吞噬途径中的 PRKCD 与认知功能和脑脊液生物标志物显著相关。Fc 受体介导的吞噬途径的鉴定表明外周固有免疫系统参与 AD 的病理生理学。PRKCD 已知与淀粉样蛋白-β诱导的神经退行性变有关。
