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.
journal_name
Celljournal_title
Cellauthors
Zhang B,Gaiteri C,Bodea LG,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,doi
10.1016/j.cell.2013.03.030subject
Has Abstractpub_date
2013-04-25 00:00:00pages
707-20issue
3eissn
0092-8674issn
1097-4172pii
S0092-8674(13)00387-5journal_volume
153pub_type
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