Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease.
Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease.
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DOI：
10.1002/alz.12468
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发表时间：
2022-06
影响因子：
14
通讯作者：
Zhang, Bin
中科院分区：
文献类型：
--
作者：
Horgusluoglu, Emrin;Neff, Ryan;Song, Won-Min;Wang, Minghui;Wang, Qian;Arnold, Matthias;Krumsiek, Jan;Galindo-Prieto, Beatriz;Ming, Chen;Nho, Kwangsik;Kastenmueller, Gabi;Han, Xianlin;Baillie, Rebecca;Zeng, Qi;Andrews, Shea;Cheng, Haoxiang;Hao, Ke;Goate, Alison;Bennett, David A.;Saykin, Andrew J.;Kaddurah-Daouk, Rima;Zhang, Bin
关键词：
代谢物是细胞过程的生化产物，可用于测量与阿尔茨海默病（AD）发病机制相关的生化途径的改变。然而，全身性代谢异常与AD发病机制之间的关系尚不清楚。在本研究中，我们旨在通过综合系统生物学框架分析AD的遗传、转录组、代谢组和蛋白质组数据，确定AD特异性代谢组变化及其潜在的上游遗传和转录调控因子。阿尔茨海默病神经影像学倡议（ADNI）中代谢物共表达网络分析的血液代谢组学数据显示，短链酰基肉碱/氨基酸和中/长链酰基肉碱与阿尔茨海默病的临床结果最相关，包括情景记忆评分和疾病严重程度。来自加速药物合作伙伴阿尔茨海默病（AMP - AD）项目的ADNI血液和大脑中的基因表达数据整合显示，ABCA1和CPT1A参与了AD中酰基肉碱和氨基酸的调节。AMP - AD脑RNA - seq数据的基因共表达网络分析表明，CPT1A和ABCA1中心的子网络分别与神经系统和免疫反应有关。在ADNI中，ABCA1基因表达和脂联素蛋白（ABCA1的调节因子）的增加与AD中短链酰基肉碱和胺的减少相对应。总之，我们对阿尔茨海默病大规模多组学数据的综合分析系统地鉴定了阿尔茨海默病中新的代谢物及其潜在的调节因子，这些发现不仅为开发阿尔茨海默病敏感和特异性的诊断生物标志物铺平了道路，而且为确定阿尔茨海默病发病的新的分子机制铺平了道路。
Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD‐specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co‐expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short‐chain acylcarnitines/amino acids and medium/long‐chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP‐AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co‐expression network analysis of the AMP‐AD brain RNA‐seq data suggests the CPT1A‐ and ABCA1‐centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short‐chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large‐scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
3.2
作者：
Crane, Paul K.;Carle, Adam;Gibbons, Laura E.;Insel, Philip;Mackin, R. Scott;Gross, Alden;Jones, Richard N.;Mukherjee, Shubhabrata;Curtis, S. McKay;Harvey, Danielle;Weiner, Michael;Mungas, Dan
通讯作者：
Mungas, Dan
影响因子：
9.8
作者：
Allen, Mariet;Carrasquillo, Minerva M.;Funk, Cory;Heavner, Benjamin D.;Zou, Fanggeng;Younkin, Curtis S.;Burgess, Jeremy D.;Chai, High-Seng;Crook, Julia;Eddy, James A.;Li, Hongdong;Logsdon, Ben;Peters, Mette A.;Dang, Kristen K.;Wang, Xue;Serie, Daniel;Wang, Chen;Thuy Nguyen;Lincoln, Sarah;Malphrus, Kimberly;Bisceglio, Gina;Li, Ma;Golde, Todd E.;Mangravite, Lara M.;Asmann, Yan;Price, Nathan D.;Petersen, Ronald C.;Graff-Radford, Neill R.;Dickson, Dennis W.;Younkin, Steven G.;Ertekin-Taner, Nilufer
通讯作者：
Ertekin-Taner, Nilufer
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
影响因子：
14
作者：
通讯作者：
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