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

TitleIntegrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2013
AuthorsZhang, B, Gaiteri, C, Bodea, L-G, Wang, Z, McElwee, J, Podtelezhnikov, AA, Zhang, C, Xie, T, Tran, L, Dobrin, R, Fluder, E, Clurman, B, Melquist, S, Narayanan, M, Suver, C, Shah, H, Mahajan, M, Gillis, T, Mysore, J, MacDonald, ME, Lamb, JR, Bennett, DA, Molony, C, Stone, DJ, Gudnason, V, Myers, AJ, Schadt, EE, Neumann, H, Zhu, J, Emilsson, V
JournalCell
Volume153
Issue3
Pagination707-20
Date Published2013 Apr 25
ISSN1097-4172
KeywordsAdaptor Proteins, Signal Transducing, Alzheimer Disease, Animals, Bayes Theorem, Brain, Gene Regulatory Networks, Humans, Membrane Proteins, Mice, Microglia
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.

DOI10.1016/j.cell.2013.03.030
Alternate JournalCell
PubMed ID23622250
PubMed Central IDPMC3677161
Grant ListR01 AG17917 / AG / NIA NIH HHS / United States
K08 AG034290 / AG / NIA NIH HHS / United States
NS032765 / NS / NINDS NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
R01 AG11101 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
R01 MH097276 / MH / NIMH NIH HHS / United States
R01 AG034504 / AG / NIA NIH HHS / United States
R01 NS032765 / NS / NINDS NIH HHS / United States
R01 AG011101 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States