TY - JOUR
T1 - Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease
AU - Beckmann, Noam D.
AU - Lin, Wei Jye
AU - Wang, Minghui
AU - Cohain, Ariella T.
AU - Charney, Alexander W.
AU - Wang, Pei
AU - Ma, Weiping
AU - Wang, Ying Chih
AU - Jiang, Cheng
AU - Audrain, Mickael
AU - Comella, Phillip H.
AU - Fakira, Amanda K.
AU - Hariharan, Siddharth P.
AU - Belbin, Gillian M.
AU - Girdhar, Kiran
AU - Levey, Allan I.
AU - Seyfried, Nicholas T.
AU - Dammer, Eric B.
AU - Duong, Duc
AU - Lah, James J.
AU - Haure-Mirande, Jean Vianney
AU - Shackleton, Ben
AU - Fanutza, Tomas
AU - Blitzer, Robert
AU - Kenny, Eimear
AU - Zhu, Jun
AU - Haroutunian, Vahram
AU - Katsel, Pavel
AU - Gandy, Sam
AU - Tu, Zhidong
AU - Ehrlich, Michelle E.
AU - Zhang, Bin
AU - Salton, Stephen R.
AU - Schadt, Eric E.
N1 - Funding Information:
We thank the participating subjects and their families who made this study possible. We also thank the Mount Sinai Brain Brank, Mount Sinai Genomics Core and Scientific Computing at the Icahn School of Medicine at Mount Sinai as well as the Accelerating Medicine Partnership: Alzheimer Disease (AMP-AD) consortium. We would like to thank A. Goel for critical reading of the manuscript. This work was supported by NIH/NIA Grants U01AG046170, HHSN271201300031, MH086499, MH083496, R01AG046170, RF1AG054014, RF1AG057440, R01AG057907, R01AG055501, U01AG046161, P50AG025688, P30NS055077, 5R01AG053960, and 5R01AG062355. 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.). 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 grant from Guangdong Science and Technology Department (2017B030314026). 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).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85089185243&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-17405-z
DO - 10.1038/s41467-020-17405-z
M3 - Article
C2 - 32770063
AN - SCOPUS:85089185243
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3942
ER -