Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease (Retracted article. See vol. 523, 2015)
Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease (Retracted article. See vol. 523, 2015)
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DOI：
10.1038/nature12415
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发表时间：
2013-08-01
期刊：
影响因子：
64.8
通讯作者：
Abeliovich, Asa
中科院分区：
文献类型：
--
作者：
Rhinn, Herve;Fujita, Ryousuke;Abeliovich, Asa
迟发性阿尔茨海默病（LOAD）的风险受到载脂蛋白E ε 4等位基因（这里称为APOE4）的存在等遗传因素以及包括衰老在内的非遗传决定因素的强烈影响。为了探究这些因素影响人脑生理和改变LOAD风险的机制，我们首先分析了未受影响的APOE4携带者和LOAD患者的全转录组大脑皮层基因表达数据。APOE4携带者的状态与一致的转录组变化有关，这种变化与LOAD基因大致相似。APOE4和LOAD转录组变化的差异共表达相关网络分析确定了一组候选核心调控介质。其中包括APBA2、FYN、RNF219和sv2a，它们编码LOAD相关淀粉样蛋白β A4前体蛋白（APP）内吞和代谢的已知或新的调节剂。此外，RNF219中的一种遗传变异被发现影响人脑中的淀粉样蛋白沉积和LOAD发病年龄。这些数据暗示APOE4相关的分子通路促进LOAD。
Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E epsilon 4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these-including APBA2, FYN, RNF219 and SV2A-encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.