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.

To investigate the molecular foundation of sporadic Alzheimer’s disease (AD), Beckmann et al. constructed multiscale causal networks on a large human AD multi-omics dataset, detecting AD-associated networks and their top predicted regulator, VGF, with extensive validation in the 5xFAD mouse model.

Details

Title
Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease
Author
Beckmann, Noam D 1 ; Wei-Jye, Lin 2 ; Wang, Minghui 3   VIAFID ORCID Logo  ; Cohain, Ariella T 1 ; Charney, Alexander W 4 ; Wang, Pei 3   VIAFID ORCID Logo  ; Ma, Weiping 3 ; Wang, Ying-Chih 5 ; Cheng, Jiang 6   VIAFID ORCID Logo  ; Audrain Mickael 7   VIAFID ORCID Logo  ; Comella, Phillip H 1 ; Fakira, Amanda K 7 ; Hariharan, Siddharth P 7   VIAFID ORCID Logo  ; Belbin, Gillian M 8 ; Girdhar Kiran 5 ; Levey, Allan I 9   VIAFID ORCID Logo  ; Seyfried, Nicholas T 10   VIAFID ORCID Logo  ; Dammer, Eric B 11   VIAFID ORCID Logo  ; Duong Duc 10 ; Lah, James J 11 ; Jean-Vianney, Haure-Mirande 12   VIAFID ORCID Logo  ; Shackleton, Ben 13 ; Fanutza Tomas 12   VIAFID ORCID Logo  ; Blitzer, Robert 14 ; Kenny Eimear 15 ; Zhu, Jun 16   VIAFID ORCID Logo  ; Haroutunian Vahram 17   VIAFID ORCID Logo  ; Katsel Pavel 18 ; Gandy, Sam 19 ; Tu Zhidong 3 ; Ehrlich, Michelle E 20 ; Zhang, Bin 3 ; Salton, Stephen R 7   VIAFID ORCID Logo  ; Schadt, Eric E 16   VIAFID ORCID Logo 

1  Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Icahn Institute of Genomics and Multiscale Biology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
2  Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X); Sun Yat-sen University, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X); Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Neuroscience, Friedman Brain Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
3  Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Icahn Institute of Genomics and Multiscale Biology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
4  Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Icahn Institute of Genomics and Multiscale Biology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Neuroscience, Friedman Brain Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Neurosurgery, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Center for Statistical Genetics, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
5  Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
6  Icahn School of Medicine at Mount Sinai, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Neuroscience, Friedman Brain Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
7  Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Neuroscience, Friedman Brain Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
8  Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Graduate School of Biomedical Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Charles Bronfman Institute of Personalized Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
9  Emory University School of Medicine, Department of Neurology and Center for Neurodegenerative Disease, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
10  Emory University School of Medicine, Department of Neurology and Center for Neurodegenerative Disease, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502); Emory University School of Medicine, Department of Biochemistry, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
11  Emory University School of Medicine, Department of Biochemistry, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
12  Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Alzheimer’s Disease Research Center, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
13  Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
14  Icahn School of Medicine at Mount Sinai, Department of Pharmacological Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
15  Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Icahn Institute of Genomics and Multiscale Biology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Charles Bronfman Institute of Personalized Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
16  Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Icahn Institute of Genomics and Multiscale Biology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Sema4, Stamford, USA (GRID:grid.59734.3c) 
17  Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Alzheimer’s Disease Research Center, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); JJ Peters VA Medical Center, Department of Psychiatry, Bronx, USA (GRID:grid.59734.3c) 
18  Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); JJ Peters VA Medical Center, Department of Psychiatry, Bronx, USA (GRID:grid.59734.3c) 
19  Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Alzheimer’s Disease Research Center, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); JJ Peters VA Medical Center, Department of Psychiatry, Bronx, USA (GRID:grid.59734.3c) 
20  Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Pediatrics, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-17405-z
ProQuest document ID
2431121327
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.