Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease

• Type of Material: Article
• Authors: Noam D. Beckmann, Icahn School of Medicine at Mount Sinai; Wei-Jye Lin, Sun Yat Sen University; Minghui Wang, Icahn School of Medicine at Mount Sinai; Ariella T. Cohain, Icahn School of Medicine at Mount Sinai; Alexander W. Charney, Icahn School of Medicine at Mount Sinai; Pei Wang, Icahn School of Medicine at Mount Sinai; Weiping Ma, Icahn School of Medicine at Mount Sinai; Ying-Chih Wang, Icahn School of Medicine at Mount Sinai; Cheng Jiang, Icahn School of Medicine at Mount Sinai; Mickael Audrain, Icahn School of Medicine at Mount Sinai; Phillip H. Comella, Icahn School of Medicine at Mount Sinai; Amanda K Fakira, Icahn School of Medicine at Mount Sinai; Siddharth P. Hariharan, Icahn School of Medicine at Mount Sinai; Gillian M. Belbin, Icahn School of Medicine at Mount Sinai; Kiran Girdhar, Icahn School of Medicine at Mount Sinai; Allan Levey, Emory University; Nicholas Seyfried, Emory University; Eric Dammer, Emory University; Duc Duong, Emory University; James Lah, Emory University; Jean-Vianney Haure-Mirande, Icahn School of Medicine at Mount Sinai; Ben Shackleton, Icahn School of Medicine at Mount Sinai; Tomas Fanutza, Icahn School of Medicine at Mount Sinai; Robert Blitzer, Icahn School of Medicine at Mount Sinai; Eimear Kenny, Icahn School of Medicine at Mount Sinai; Jun Zhu, Icahn School of Medicine at Mount Sinai; Vahram Haroutunian, Icahn School of Medicine at Mount Sinai; Pavel Katsel, Icahn School of Medicine at Mount Sinai; Sam Gandy, Icahn School of Medicine at Mount Sinai; Zhidong Tu, Icahn School of Medicine at Mount Sinai; Michelle E. Ehrlich, Icahn School of Medicine at Mount Sinai; Bin Zhang, Icahn School of Medicine at Mount Sinai; Stephen R. Salton, Icahn School of Medicine at Mount Sinai; Eric E. Schadt, Icahn School of Medicine at Mount Sinai
• Language: English
• Date: 2020-08-07
• Publisher: Nature Research
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-17405-z
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 3942
• End Page: 3942
• Grant/Funding Information: P.W. and W.M. are partly supported by Grant U24-29CA 210093, from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC).; W.-J.L. was supported by grants from Guangdong Science and 1715 Technology Department (2017B030314026), National Natural Science Foundation of China (No. 81972967), Natural Science Foundation of Guangdong Province (2019A1515011754).; W.-J.L. was supported by grant from Guangdong Science and Technology Department (2017B030314026).; This project was also supported by the BrightFocus Foundation (S.R.S. and M.A.), the Alzheimer’s Drug Discovery Foundation (S.R.S.), and the Cure Alzheimer’s Fund (M.E.E. and S.R.S.).; This work was supported by NIH/NIA Grants U01AG046170, HHSN271201300031, MH086499, MH083496, R01AG046170, RF1AG054014, RF1AG057440, R01AG057907, R01AG055501, U01AG046161, P50AG025688, P30NS055077, 5R01AG053960, and 5R01AG062355.
• Keywords: Memory; A-beta; Amyloid beta; Neurogenesis; Protein; TAU; Mice; Multidisciplinary Sciences; Science & Technology; Gene expression; Mouse models; Integrative genomics approach; Science & Technology - Other Topics
• Research Categories: Health Sciences, Pharmacology; Engineering, Biomedical; Biology, Genetics; Biology, Neuroscience

Abstract

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer’s disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.