Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease

By Bin Zhang, Chris Gaiteri, L. Bodea, Zhi Wang, J. McElwee, A. Podtelezhnikov, Chunsheng Zhang, Tao Xie, L. Tran, Radu Dobrin and 20 more. Cell, 2013

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SUMMARY 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 1647 post-mortem brain tissues from LOAD patients and non-demented subjects, and 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 dominated by genes involved in pathogen phagocytosis, containing TYROBP as a key regulator and up-regulated in LOAD. Mouse microglia cells over-expressing 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 novel framework to test models of disease mechanisms underlying LOAD.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/b8fe1ad88938f76cbd72d4c4751927a21a542f0a

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Citations in the corpus

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