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October 2021; 7 (5) ArticleOpen Access

Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease

View ORCID ProfileZachary F. Gerring, Eric R. Gamazon, Anthony White, Eske M. Derks
First published September 13, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000622
Zachary F. Gerring
From the Translational Neurogenomics Laboratory (Z.F.G., E.M.D.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Division of Genetic Medicine (E.R.G.), Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN; and Cellular and Molecular Neurodegeneration (A.W.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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  • ORCID record for Zachary F. Gerring
Eric R. Gamazon
From the Translational Neurogenomics Laboratory (Z.F.G., E.M.D.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Division of Genetic Medicine (E.R.G.), Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN; and Cellular and Molecular Neurodegeneration (A.W.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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  • For correspondence: eric.gamazon@vumc.org
Anthony White
From the Translational Neurogenomics Laboratory (Z.F.G., E.M.D.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Division of Genetic Medicine (E.R.G.), Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN; and Cellular and Molecular Neurodegeneration (A.W.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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  • For correspondence: tony.white@qimrberghofer.edu.au
Eske M. Derks
From the Translational Neurogenomics Laboratory (Z.F.G., E.M.D.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Division of Genetic Medicine (E.R.G.), Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN; and Cellular and Molecular Neurodegeneration (A.W.), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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  • For correspondence: eske.derks@qimrberghofer.edu.au
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Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease
Zachary F. Gerring, Eric R. Gamazon, Anthony White, Eske M. Derks
Neurol Genet Oct 2021, 7 (5) e622; DOI: 10.1212/NXG.0000000000000622

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Abstract

Background and Objectives To integrate genome-wide association study data with tissue-specific gene expression information to identify coexpression networks, biological pathways, and drug repositioning candidates for Alzheimer disease.

Methods We integrated genome-wide association summary statistics for Alzheimer disease with tissue-specific gene coexpression networks from brain tissue samples in the Genotype-Tissue Expression study. We identified gene coexpression networks enriched with genetic signals for Alzheimer disease and characterized the associated networks using biological pathway analysis. The disease-implicated modules were subsequently used as a molecular substrate for a computational drug repositioning analysis, in which we (1) imputed genetically regulated gene expression within Alzheimer disease implicated modules; (2) integrated the imputed gene expression levels with drug-gene signatures from the connectivity map to identify compounds that normalize dysregulated gene expression underlying Alzheimer disease; and (3) prioritized drug compounds and mechanisms of action based on the extent to which they normalize dysregulated expression signatures.

Results Genetic factors for Alzheimer disease are enriched in brain gene coexpression networks involved in the immune response. Computational drug repositioning analyses of expression changes within the disease-associated networks retrieved known Alzheimer disease drugs (e.g., memantine) as well as biologically meaningful drug categories (e.g., glutamate receptor antagonists).

Discussion Our results improve the biological interpretation of genetic data for Alzheimer disease and provide a list of potential antidementia drug repositioning candidates for which the efficacy should be investigated in functional validation studies.

Glossary

CMap=
Connectivity Map;
eQTL=
expression quantitative trait loci;
GTEx=
Genotype-Tissue Expression;
GWAS=
genome-wide association study;
LD=
linkage disequilibrium;
MOA=
mechanism of action;
NSAID=
nonsteroidal anti-inflammatory drug;
RPKM=
Reads Per Kilobase of transcript, per Million mapped reads;
SNP=
single nucleotide polymorphism;
UKBB=
UK Biobank;
WGCNA=
weighted gene coexpression network analysis

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • Received January 31, 2021.
  • Accepted in final form July 13, 2021.
  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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