Identification of novel drug targets for Alzheimer's disease by integrating genetics and proteomes from brain and blood
Identification of novel drug targets for Alzheimer's disease by integrating genetics and proteomes from brain and blood
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通过整合来自大脑和血液的遗传学和蛋白质组来识别阿尔茨海默病的新药物靶点。
DOI：
10.1038/s41380-021-01251-6
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发表时间：
2021-08-11
影响因子：
11
通讯作者：
Yu, Jin-Tai
中科院分区：
文献类型：
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作者：
Ou, Ya-Nan;Yang, Yu-Xiang;Yu, Jin-Tai
全基因组关联研究（GWAS）已经发现了许多阿尔茨海默病（AD）的风险基因，但这些基因如何赋予AD风险是具有挑战性的。为了有效地将遗传关联转化为AD的药物靶点，我们采用了一种综合分析管道，通过系统地应用蛋白质组关联研究（PWAS），孟德尔随机化（MR）和贝叶斯共定位，使用大脑和血液中的蛋白质组。总的来说，我们鉴定了7个基因（ACE、ICA 1 L、TOM 1 L2、SNX 32、EPHX 2、CTSH和RTFDC 1）的脑蛋白丰度在AD中是因果性的（P < 0.05/PWAS和MR鉴定的蛋白质; PPH 4>80%用于贝叶斯共定位）。这些基因编码的蛋白质主要表达于海马神经元和星形胶质细胞表面。其中，ACE及其蛋白质丰度也被鉴定为与基于血液的研究中的AD显著相关，并且在转录组水平上显示出显著性。还发现SNX 32在血液转录组水平上与AD相关。总的来说，我们目前对遗传学、蛋白质组学和转录组学方法的研究结果已经确定了引人注目的基因，这可能为设计未来的AD功能研究和潜在的药物靶点提供重要的线索。
Genome-wide association studies (GWASs) have discovered numerous risk genes for Alzheimer's disease (AD), but how these genes confer AD risk is challenging to decipher. To efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using proteomes in the brain and blood by systematically applying proteome-wide association study (PWAS), Mendelian randomization (MR) and Bayesian colocalization. Collectively, we identified the brain protein abundance of 7 genes (ACE, ICA1L, TOM1L2, SNX32, EPHX2, CTSH, and RTFDC1) are causal in AD (P < 0.05/proteins identified for PWAS and MR; PPH4 >80% for Bayesian colocalization). The proteins encoded by these genes were mainly expressed on the surface of glutamatergic neurons and astrocytes. Of them, ACE with its protein abundance was also identified in significant association with AD on the blood-based studies and showed significance at the transcriptomic level. SNX32 was also found to be associated with AD at the blood transcriptomic level. Collectively, our current study results on genetic, proteomic, and transcriptomic approaches has identified compelling genes, which may provide important leads to design future functional studies and potential drug targets for AD.