Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease.
Cell
; 153(3): 707-20, 2013 Apr 25.
Article
en En
| MEDLINE
| ID: mdl-23622250
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Redes Reguladoras de Genes
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Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos