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; Eric E. Schadt

doi:10.1038/s41467-020-17405-z

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. LahJean 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, Eric E. Schadt

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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.

Original language	English
Article number	3942
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17405-z
State	Published - 1 Dec 2020

Access to Document

10.1038/s41467-020-17405-z

Cite this

Beckmann, N. D., Lin, W. J., Wang, M., Cohain, A. T., Charney, A. W., Wang, P., Ma, W., Wang, Y. C., Jiang, C., Audrain, M., Comella, P. H., Fakira, A. K., Hariharan, S. P., Belbin, G. M., Girdhar, K., Levey, A. I., Seyfried, N. T., Dammer, E. B., Duong, D., ... Schadt, E. E. (2020). Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease. Nature Communications, 11(1), [3942]. https://doi.org/10.1038/s41467-020-17405-z

@article{c3ea62c1ea2d4381bfd4eca693beaa36,

title = "Multiscale causal networks identify VGF as a key regulator of Alzheimer{\textquoteright}s disease",

abstract = "Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer{\textquoteright}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.",

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

note = "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{\textquoteright}s Drug Discovery Foundation (S.R.S.), and the Cure Alzheimer{\textquoteright}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: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-17405-z",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Beckmann, ND, Lin, WJ, Wang, M, Cohain, AT, Charney, AW , Wang, P, Ma, W, Wang, YC, Jiang, C, Audrain, M, Comella, PH, Fakira, AK, Hariharan, SP, Belbin, GM, Girdhar, K, Levey, AI, Seyfried, NT, Dammer, EB, Duong, D, Lah, JJ, Haure-Mirande, JV, Shackleton, B, Fanutza, T, Blitzer, R, Kenny, E, Zhu, J, Haroutunian, V , Katsel, P , Gandy, S, Tu, Z, Ehrlich, ME, Zhang, B, Salton, SR & Schadt, EE 2020, 'Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease', Nature Communications, vol. 11, no. 1, 3942. https://doi.org/10.1038/s41467-020-17405-z

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 -

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

Abstract

Access to Document

Fingerprint

Cite this