Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease

Bin Zhang; Chris Gaiteri; Liviu-Gabriel Bodea; Zhi Wang; Joshua McElwee; Alexei A Podtelezhnikov; Chunsheng Zhang; Tao Xie; Linh Tran; Radu Dobrin; Eugene Fluder; Bruce Clurman; Stacey Melquist; Manikandan Narayanan; Christine Suver; Hardik Shah; Milind Mahajan; Tammy Gillis; Jayalakshmi Mysore; Marcy E MacDonald; John R Lamb; David A Bennett; Cliona Molony; David J Stone; Vilmundur Gudnason; Amanda J Myers; Eric E Schadt; Harald Neumann; Jun Zhu; Valur Emilsson

doi:10.1016/j.cell.2013.03.030

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Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease

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Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease

Bin Zhang, Chris Gaiteri, Liviu-Gabriel Bodea, Zhi Wang, Joshua McElwee, Alexei A Podtelezhnikov, Chunsheng Zhang, Tao Xie, Linh Tran, Radu Dobrin, …

Cell (Cambridge), Vol.153(3), pp.707-720

2013-04-25

DOI: https://doi.org/10.1016/j.cell.2013.03.030

PMCID: PMC3677161

PMID: 23622250

Abstract

The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD. [Display omitted] •Systems approach to LOAD based on large-scale human brain-tissue sampling•Molecular networks show strong remodeling effect in LOAD brains•Integrative network-based analysis implicates the immune/microglia network in LOAD•TYROBP implicated as key causal regulator within the immune/microglia module An integrated systems approach leverages transcriptome data from postmortem brains of late-onset Alzheimer’s disease patients to identify key nodes that drive dysregulated or rewired networks in the disease state.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease
Creators: Bin Zhang - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
Chris Gaiteri - Sage Bionetworks, 1100 Fairview Avenue North, Seattle, WA 98109, USA
Liviu-Gabriel Bodea - Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Zhi Wang - Sage Bionetworks, 1100 Fairview Avenue North, Seattle, WA 98109, USA
Joshua McElwee - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Alexei A Podtelezhnikov - Merck Research Laboratories, Merck & Co. Inc., 770 Sumneytown Pike, WP53B-120 West Point, PA 19486, USA
Chunsheng Zhang - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Tao Xie - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Linh Tran - Sage Bionetworks, 1100 Fairview Avenue North, Seattle, WA 98109, USA
Radu Dobrin - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Eugene Fluder - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Bruce Clurman - Fred Hutch Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA
Stacey Melquist - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Manikandan Narayanan - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Christine Suver - Sage Bionetworks, 1100 Fairview Avenue North, Seattle, WA 98109, USA
Hardik Shah - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
Milind Mahajan - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
Tammy Gillis - Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Jayalakshmi Mysore - Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Marcy E MacDonald - Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
John R Lamb - GNF Novartis, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
David A Bennett - Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
Cliona Molony - Merck Research Laboratories, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA
David J Stone - Merck Research Laboratories, Merck & Co. Inc., 770 Sumneytown Pike, WP53B-120 West Point, PA 19486, USA
Vilmundur Gudnason - Icelandic Heart Association and University of Iceland, Holtasmari 1, IS-201 Kopavogur, Iceland
Amanda J Myers - Department of Psychiatry and Behavioral Sciences, Division of Neuroscience, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Eric E Schadt - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
Harald Neumann - Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Jun Zhu - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
Valur Emilsson - Icelandic Heart Association and University of Iceland, Holtasmari 1, IS-201 Kopavogur, Iceland
Publication Details: Cell (Cambridge), Vol.153(3), pp.707-720
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; Cell Biology Research
Language: English
Resource Type: Journal article
PMID: 23622250
PMCID: PMC3677161
Record Identifier: 991031561865102976