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

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.

DOI: 10.1016/j.cell.2013.03.030

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@article{Zhang2013IntegratedSA, title={Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease}, author={Bin Zhang and Chris Gaiteri and Liviu-Gabriel Bodea and Zhi Long Wang and Joshua J McElwee and Alexei A. Podtelezhnikov and Chunsheng Zhang and Tao Xie and Linh M. Tran and Radu Dobrin and Eugene Fluder and Bruce E. Clurman and Stacey Melquist and Manikandan Narayanan and Christine Suver and Hardik Shah and Milind Mahajan and Tammy Gillis and Jayalakshmi Srinidhi Mysore and Marcy E. MacDonald and John R. Lamb and David A. Bennett and Cliona Molony and David J. Stone and Vilmundur Gudnason and Amanda Myers and Eric E. Schadt and Harald Neumann and Jun Zhu and Valur Emilsson}, journal={Cell}, year={2013}, volume={153}, pages={707-720} }