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

Noam D. Beckmann, Wei-Jye Lin, Minghui Wang, Ariella T. Cohain, Alexander W. Charney, Pei Wang, Weiping Ma, Ying-Chih Wang, Cheng Jiang, Mickael Audrain, Phillip H. Comella, Amanda K. Fakira, Siddharth P. Hariharan, Gillian M. Belbin, Kiran Girdhar, Allan I. Levey, Nicholas T. Seyfried, Eric B. Dammer, Duc Duong, James J. Lah, Jean-Vianney Haure-Mirande, Ben Shackleton, Tomas Fanutza, Robert Blitzer, Eimear Kenny, Jun Zhu, Vahram Haroutunian, Pavel Katsel, Sam Gandy, Zhidong Tu, Michelle E. Ehrlich, Bin Zhang, Stephen R. Salton () and Eric E. Schadt ()
Additional contact information
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 I. Levey: Emory University School of Medicine
Nicholas T. Seyfried: Emory University School of Medicine
Eric B. Dammer: Emory University School of Medicine
Duc Duong: Emory University School of Medicine
James J. Lah: Emory University School of Medicine
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

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17405-z

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