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

• Published in: Cell Vol. 153; no. 3; pp. 707 - 720
• Main Authors: Zhang, Bin, Gaiteri, Chris, Bodea, Liviu-Gabriel, Wang, Zhi, McElwee, Joshua, Podtelezhnikov, Alexei A., Zhang, Chunsheng, Xie, Tao, Tran, Linh, Dobrin, Radu, Fluder, Eugene, Clurman, Bruce, Melquist, Stacey, Narayanan, Manikandan, Suver, Christine, Shah, Hardik, Mahajan, Milind, Gillis, Tammy, Mysore, Jayalakshmi, MacDonald, Marcy E., Lamb, John R., Bennett, David A., Molony, Cliona, Stone, David J., Gudnason, Vilmundur, Myers, Amanda J., Schadt, Eric E., Neumann, Harald, Zhu, Jun, Emilsson, Valur
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2013
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Alzheimer disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Animals; Bayes Theorem; brain; Brain - metabolism; Brain - pathology; chemical structure; disease models; gene expression regulation; Gene Regulatory Networks; genes; Humans; Membrane Proteins - metabolism; Mice; Microglia - metabolism; neuroglia; pathogens; patients; phagocytosis; tissues
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2013.03.030

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.