Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Vivek Swarup; Flora I. Hinz; Jessica E. Rexach; Ken ichi Noguchi; Hiroyoshi Toyoshiba; Akira Oda; Keisuke Hirai; Arjun Sarkar; Nicholas T. Seyfried; Chialin Cheng; Stephen J. Haggarty; Raffaele Ferrari; Jonathan D. Rohrer; Adaikalavan Ramasamy; John Hardy; Dena G. Hernandez; Michael A. Nalls; Andrew B. Singleton; John B.J. Kwok; Carol Dobson-Stone; William S. Brooks; Peter R. Schofield; Glenda M. Halliday; John R. Hodges; Olivier Piguet; Lauren Bartley; Elizabeth Thompson; Eric Haan; Isabel Hernández; Agustín Ruiz; Mercè Boada; Barbara Borroni; Alessandro Padovani; Nigel J. Cairns; Carlos Cruchaga; Giuliano Binetti; Roberta Ghidoni; Luisa Benussi; Gianluigi Forloni; Diego Albani; Daniela Galimberti; Chiara Fenoglio; Maria Serpente; Elio Scarpini; Jordi Clarimón; Alberto Lleó; Rafael Blesa; Maria Landqvist Waldö; Karin Nilsson; Christer Nilsson; Ian R.A. Mackenzie; Ging Yuek R. Hsiung; David M.A. Mann; Jordan Grafman; Christopher M. Morris; Johannes Attems; Timothy D. Griffiths; Ian G. McKeith; Alan J. Thomas; Evelyn Jaros; Pietro Pietrini; Edward D. Huey; Eric M. Wassermann; Michael C. Tierney; Atik Baborie; Pau Pastor; Sara Ortega-Cubero; Cristina Razquin; Elena Alonso; Robert Perneczky; Janine Diehl-Schmid; Panagiotis Alexopoulos; Alexander Kurz; Innocenzo Rainero; Elisa Rubino; Lorenzo Pinessi; Ekaterina Rogaeva; Peter St George-Hyslop; Giacomina Rossi; Fabrizio Tagliavini; Giorgio Giaccone; James B. Rowe; Johannes C.M. Schlachetzki; James Uphill; John Collinge; Simon Mead; Adrian Danek; Vivianna M. Van Deerlin; Murray Grossman; John Q. Trojanowski; Stuart Pickering-Brown; Parastoo Momeni; Julie van der Zee; Marc Cruts; Christine Van Broeckhoven; Stefano F. Cappa; Isabelle Leber; Alexis Brice; Didier Hannequin; Véronique Golfier

doi:10.1038/s41591-018-0223-3

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Vivek Swarup, Flora I. Hinz, Jessica E. Rexach, Ken ichi Noguchi, Hiroyoshi Toyoshiba, Akira Oda, Keisuke Hirai, Arjun Sarkar, Nicholas T. Seyfried, Chialin Cheng, Stephen J. Haggarty, Raffaele Ferrari, Jonathan D. Rohrer, Adaikalavan Ramasamy, John Hardy, Dena G. Hernandez, Michael A. Nalls, Andrew B. Singleton, John B.J. Kwok, Carol Dobson-StoneWilliam S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Nigel J. Cairns, Carlos Cruchaga, Giuliano Binetti, Roberta Ghidoni, Luisa Benussi, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R.A. Mackenzie, Ging Yuek R. Hsiung, David M.A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan J. Thomas, Evelyn Jaros, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Michael C. Tierney, Atik Baborie, Pau Pastor, Sara Ortega-Cubero, Cristina Razquin, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B. Rowe, Johannes C.M. Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M. Van Deerlin, Murray Grossman, John Q. Trojanowski, Stuart Pickering-Brown, Parastoo Momeni, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Leber, Alexis Brice, Didier Hannequin, Véronique Golfier

Research output: Contribution to journal › Article › Research

24 Citations (Scopus)

Abstract

© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Original language	English
Pages (from-to)	152-164
Journal	Nature Medicine
Volume	25
DOIs	https://doi.org/10.1038/s41591-018-0223-3
Publication status	Published - 1 Jan 2019

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Swarup, V., Hinz, F. I., Rexach, J. E., Noguchi, K. I., Toyoshiba, H., Oda, A., Hirai, K., Sarkar, A., Seyfried, N. T., Cheng, C., Haggarty, S. J., Ferrari, R., Rohrer, J. D., Ramasamy, A., Hardy, J., Hernandez, D. G., Nalls, M. A., Singleton, A. B., Kwok, J. B. J., ... Golfier, V. (2019). Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. Nature Medicine, 25, 152-164. https://doi.org/10.1038/s41591-018-0223-3

Swarup, Vivek ; Hinz, Flora I. ; Rexach, Jessica E. ; Noguchi, Ken ichi ; Toyoshiba, Hiroyoshi ; Oda, Akira ; Hirai, Keisuke ; Sarkar, Arjun ; Seyfried, Nicholas T. ; Cheng, Chialin ; Haggarty, Stephen J. ; Ferrari, Raffaele ; Rohrer, Jonathan D. ; Ramasamy, Adaikalavan ; Hardy, John ; Hernandez, Dena G. ; Nalls, Michael A. ; Singleton, Andrew B. ; Kwok, John B.J. ; Dobson-Stone, Carol ; Brooks, William S. ; Schofield, Peter R. ; Halliday, Glenda M. ; Hodges, John R. ; Piguet, Olivier ; Bartley, Lauren ; Thompson, Elizabeth ; Haan, Eric ; Hernández, Isabel ; Ruiz, Agustín ; Boada, Mercè ; Borroni, Barbara ; Padovani, Alessandro ; Cairns, Nigel J. ; Cruchaga, Carlos ; Binetti, Giuliano ; Ghidoni, Roberta ; Benussi, Luisa ; Forloni, Gianluigi ; Albani, Diego ; Galimberti, Daniela ; Fenoglio, Chiara ; Serpente, Maria ; Scarpini, Elio ; Clarimón, Jordi ; Lleó, Alberto ; Blesa, Rafael ; Waldö, Maria Landqvist ; Nilsson, Karin ; Nilsson, Christer ; Mackenzie, Ian R.A. ; Hsiung, Ging Yuek R. ; Mann, David M.A. ; Grafman, Jordan ; Morris, Christopher M. ; Attems, Johannes ; Griffiths, Timothy D. ; McKeith, Ian G. ; Thomas, Alan J. ; Jaros, Evelyn ; Pietrini, Pietro ; Huey, Edward D. ; Wassermann, Eric M. ; Tierney, Michael C. ; Baborie, Atik ; Pastor, Pau ; Ortega-Cubero, Sara ; Razquin, Cristina ; Alonso, Elena ; Perneczky, Robert ; Diehl-Schmid, Janine ; Alexopoulos, Panagiotis ; Kurz, Alexander ; Rainero, Innocenzo ; Rubino, Elisa ; Pinessi, Lorenzo ; Rogaeva, Ekaterina ; George-Hyslop, Peter St ; Rossi, Giacomina ; Tagliavini, Fabrizio ; Giaccone, Giorgio ; Rowe, James B. ; Schlachetzki, Johannes C.M. ; Uphill, James ; Collinge, John ; Mead, Simon ; Danek, Adrian ; Van Deerlin, Vivianna M. ; Grossman, Murray ; Trojanowski, John Q. ; Pickering-Brown, Stuart ; Momeni, Parastoo ; van der Zee, Julie ; Cruts, Marc ; Van Broeckhoven, Christine ; Cappa, Stefano F. ; Leber, Isabelle ; Brice, Alexis ; Hannequin, Didier ; Golfier, Véronique. / Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. In: Nature Medicine. 2019 ; Vol. 25. pp. 152-164.

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title = "Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia",

abstract = "{\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.",

author = "Vivek Swarup and Hinz, {Flora I.} and Rexach, {Jessica E.} and Noguchi, {Ken ichi} and Hiroyoshi Toyoshiba and Akira Oda and Keisuke Hirai and Arjun Sarkar and Seyfried, {Nicholas T.} and Chialin Cheng and Haggarty, {Stephen J.} and Raffaele Ferrari and Rohrer, {Jonathan D.} and Adaikalavan Ramasamy and John Hardy and Hernandez, {Dena G.} and Nalls, {Michael A.} and Singleton, {Andrew B.} and Kwok, {John B.J.} and Carol Dobson-Stone and Brooks, {William S.} and Schofield, {Peter R.} and Halliday, {Glenda M.} and Hodges, {John R.} and Olivier Piguet and Lauren Bartley and Elizabeth Thompson and Eric Haan and Isabel Hern{\'a}ndez and Agust{\'i}n Ruiz and Merc{\`e} Boada and Barbara Borroni and Alessandro Padovani and Cairns, {Nigel J.} and Carlos Cruchaga and Giuliano Binetti and Roberta Ghidoni and Luisa Benussi and Gianluigi Forloni and Diego Albani and Daniela Galimberti and Chiara Fenoglio and Maria Serpente and Elio Scarpini and Jordi Clarim{\'o}n and Alberto Lle{\'o} and Rafael Blesa and Wald{\"o}, {Maria Landqvist} and Karin Nilsson and Christer Nilsson and Mackenzie, {Ian R.A.} and Hsiung, {Ging Yuek R.} and Mann, {David M.A.} and Jordan Grafman and Morris, {Christopher M.} and Johannes Attems and Griffiths, {Timothy D.} and McKeith, {Ian G.} and Thomas, {Alan J.} and Evelyn Jaros and Pietro Pietrini and Huey, {Edward D.} and Wassermann, {Eric M.} and Tierney, {Michael C.} and Atik Baborie and Pau Pastor and Sara Ortega-Cubero and Cristina Razquin and Elena Alonso and Robert Perneczky and Janine Diehl-Schmid and Panagiotis Alexopoulos and Alexander Kurz and Innocenzo Rainero and Elisa Rubino and Lorenzo Pinessi and Ekaterina Rogaeva and George-Hyslop, {Peter St} and Giacomina Rossi and Fabrizio Tagliavini and Giorgio Giaccone and Rowe, {James B.} and Schlachetzki, {Johannes C.M.} and James Uphill and John Collinge and Simon Mead and Adrian Danek and {Van Deerlin}, {Vivianna M.} and Murray Grossman and Trojanowski, {John Q.} and Stuart Pickering-Brown and Parastoo Momeni and {van der Zee}, Julie and Marc Cruts and {Van Broeckhoven}, Christine and Cappa, {Stefano F.} and Isabelle Leber and Alexis Brice and Didier Hannequin and V{\'e}ronique Golfier",

year = "2019",

month = jan,

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doi = "10.1038/s41591-018-0223-3",

language = "English",

volume = "25",

pages = "152--164",

journal = "Nature Medicine",

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Swarup, V, Hinz, FI, Rexach, JE, Noguchi, KI, Toyoshiba, H, Oda, A, Hirai, K, Sarkar, A, Seyfried, NT, Cheng, C, Haggarty, SJ, Ferrari, R, Rohrer, JD, Ramasamy, A, Hardy, J, Hernandez, DG, Nalls, MA, Singleton, AB, Kwok, JBJ, Dobson-Stone, C, Brooks, WS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cairns, NJ, Cruchaga, C, Binetti, G, Ghidoni, R, Benussi, L, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A , Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Jaros, E, Pietrini, P, Huey, ED, Wassermann, EM, Tierney, MC, Baborie, A, Pastor, P, Ortega-Cubero, S, Razquin, C, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, PS, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, Pickering-Brown, S, Momeni, P, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, SF, Leber, I, Brice, A, Hannequin, D & Golfier, V 2019, 'Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia', Nature Medicine, vol. 25, pp. 152-164. https://doi.org/10.1038/s41591-018-0223-3

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. / Swarup, Vivek; Hinz, Flora I.; Rexach, Jessica E.; Noguchi, Ken ichi; Toyoshiba, Hiroyoshi; Oda, Akira; Hirai, Keisuke; Sarkar, Arjun; Seyfried, Nicholas T.; Cheng, Chialin; Haggarty, Stephen J.; Ferrari, Raffaele; Rohrer, Jonathan D.; Ramasamy, Adaikalavan; Hardy, John; Hernandez, Dena G.; Nalls, Michael A.; Singleton, Andrew B.; Kwok, John B.J.; Dobson-Stone, Carol; Brooks, William S.; Schofield, Peter R.; Halliday, Glenda M.; Hodges, John R.; Piguet, Olivier; Bartley, Lauren; Thompson, Elizabeth; Haan, Eric; Hernández, Isabel; Ruiz, Agustín; Boada, Mercè; Borroni, Barbara; Padovani, Alessandro; Cairns, Nigel J.; Cruchaga, Carlos; Binetti, Giuliano; Ghidoni, Roberta; Benussi, Luisa; Forloni, Gianluigi; Albani, Diego; Galimberti, Daniela; Fenoglio, Chiara; Serpente, Maria; Scarpini, Elio; Clarimón, Jordi; Lleó, Alberto ; Blesa, Rafael; Waldö, Maria Landqvist; Nilsson, Karin; Nilsson, Christer; Mackenzie, Ian R.A.; Hsiung, Ging Yuek R.; Mann, David M.A.; Grafman, Jordan; Morris, Christopher M.; Attems, Johannes; Griffiths, Timothy D.; McKeith, Ian G.; Thomas, Alan J.; Jaros, Evelyn; Pietrini, Pietro; Huey, Edward D.; Wassermann, Eric M.; Tierney, Michael C.; Baborie, Atik; Pastor, Pau; Ortega-Cubero, Sara; Razquin, Cristina; Alonso, Elena; Perneczky, Robert; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Kurz, Alexander; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Rogaeva, Ekaterina; George-Hyslop, Peter St; Rossi, Giacomina; Tagliavini, Fabrizio; Giaccone, Giorgio; Rowe, James B.; Schlachetzki, Johannes C.M.; Uphill, James; Collinge, John; Mead, Simon; Danek, Adrian; Van Deerlin, Vivianna M.; Grossman, Murray; Trojanowski, John Q.; Pickering-Brown, Stuart; Momeni, Parastoo; van der Zee, Julie; Cruts, Marc; Van Broeckhoven, Christine; Cappa, Stefano F.; Leber, Isabelle; Brice, Alexis; Hannequin, Didier; Golfier, Véronique.

In: Nature Medicine, Vol. 25, 01.01.2019, p. 152-164.

Research output: Contribution to journal › Article › Research

TY - JOUR

T1 - Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

AU - Swarup, Vivek

AU - Hinz, Flora I.

AU - Rexach, Jessica E.

AU - Noguchi, Ken ichi

AU - Toyoshiba, Hiroyoshi

AU - Oda, Akira

AU - Hirai, Keisuke

AU - Sarkar, Arjun

AU - Seyfried, Nicholas T.

AU - Cheng, Chialin

AU - Haggarty, Stephen J.

AU - Ferrari, Raffaele

AU - Rohrer, Jonathan D.

AU - Ramasamy, Adaikalavan

AU - Hardy, John

AU - Hernandez, Dena G.

AU - Nalls, Michael A.

AU - Singleton, Andrew B.

AU - Kwok, John B.J.

AU - Dobson-Stone, Carol

AU - Brooks, William S.

AU - Schofield, Peter R.

AU - Halliday, Glenda M.

AU - Hodges, John R.

AU - Piguet, Olivier

AU - Bartley, Lauren

AU - Thompson, Elizabeth

AU - Haan, Eric

AU - Hernández, Isabel

AU - Ruiz, Agustín

AU - Boada, Mercè

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Cairns, Nigel J.

AU - Cruchaga, Carlos

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Benussi, Luisa

AU - Forloni, Gianluigi

AU - Albani, Diego

AU - Galimberti, Daniela

AU - Fenoglio, Chiara

AU - Serpente, Maria

AU - Scarpini, Elio

AU - Clarimón, Jordi

AU - Lleó, Alberto

AU - Blesa, Rafael

AU - Waldö, Maria Landqvist

AU - Nilsson, Karin

AU - Nilsson, Christer

AU - Mackenzie, Ian R.A.

AU - Hsiung, Ging Yuek R.

AU - Mann, David M.A.

AU - Grafman, Jordan

AU - Morris, Christopher M.

AU - Attems, Johannes

AU - Griffiths, Timothy D.

AU - McKeith, Ian G.

AU - Thomas, Alan J.

AU - Jaros, Evelyn

AU - Pietrini, Pietro

AU - Huey, Edward D.

AU - Wassermann, Eric M.

AU - Tierney, Michael C.

AU - Baborie, Atik

AU - Pastor, Pau

AU - Ortega-Cubero, Sara

AU - Razquin, Cristina

AU - Alonso, Elena

AU - Perneczky, Robert

AU - Diehl-Schmid, Janine

AU - Alexopoulos, Panagiotis

AU - Kurz, Alexander

AU - Rainero, Innocenzo

AU - Rubino, Elisa

AU - Pinessi, Lorenzo

AU - Rogaeva, Ekaterina

AU - George-Hyslop, Peter St

AU - Rossi, Giacomina

AU - Tagliavini, Fabrizio

AU - Giaccone, Giorgio

AU - Rowe, James B.

AU - Schlachetzki, Johannes C.M.

AU - Uphill, James

AU - Collinge, John

AU - Mead, Simon

AU - Danek, Adrian

AU - Van Deerlin, Vivianna M.

AU - Grossman, Murray

AU - Trojanowski, John Q.

AU - Pickering-Brown, Stuart

AU - Momeni, Parastoo

AU - van der Zee, Julie

AU - Cruts, Marc

AU - Van Broeckhoven, Christine

AU - Cappa, Stefano F.

AU - Leber, Isabelle

AU - Brice, Alexis

AU - Hannequin, Didier

AU - Golfier, Véronique

PY - 2019/1/1

Y1 - 2019/1/1

N2 - © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

AB - © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

U2 - 10.1038/s41591-018-0223-3

DO - 10.1038/s41591-018-0223-3

M3 - Article

C2 - 30510257

VL - 25

SP - 152

EP - 164

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

ER -