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

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 and Emilsson, Valur (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell, 153 3: 707-720. doi:10.1016/j.cell.2013.03.030

Author 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
Title Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease
Journal name Cell   Check publisher's open access policy
ISSN 0092-8674
Publication date 2013-04-25
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.cell.2013.03.030
Open Access Status Not yet assessed
Volume 153
Issue 3
Start page 707
End page 720
Total pages 14
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
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.
Keyword Biochemistry & Molecular Biology
Cell Biology
Biochemistry & Molecular Biology
Cell Biology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID FOR1336
R01 AG034504
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Centre for Ageing Dementia Research Publications
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