title: 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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. bin.zhang@mssm.edu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Chris
authors.initials: C
authors.lastname: Gaiteri
authors.forename: Liviu-Gabriel
authors.initials: LG
authors.lastname: Bodea
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.forename: Joshua
authors.initials: J
authors.lastname: McElwee
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Podtelezhnikov
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Linh
authors.initials: L
authors.lastname: Tran
authors.forename: Radu
authors.initials: R
authors.lastname: Dobrin
authors.forename: Eugene
authors.initials: E
authors.lastname: Fluder
authors.forename: Bruce
authors.initials: B
authors.lastname: Clurman
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.forename: Manikandan
authors.initials: M
authors.lastname: Narayanan
authors.forename: Christine
authors.initials: C
authors.lastname: Suver
authors.forename: Hardik
authors.initials: H
authors.lastname: Shah
authors.forename: Milind
authors.initials: M
authors.lastname: Mahajan
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Mysore
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: John R
authors.initials: JR
authors.lastname: Lamb
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Cliona
authors.initials: C
authors.lastname: Molony
authors.forename: David J
authors.initials: DJ
authors.lastname: Stone
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Valur
authors.initials: V
authors.lastname: Emilsson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001499:Bayes Theorem; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D053263:Gene Regulatory Networks; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C110546:TYROBP protein, human