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Systems biology approach to late‐onset Alzheimer's disease genome‐wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments
Author(s) -
Mukherjee Shubhabrata,
Russell Joshua C.,
Carr Daniel T.,
Burgess Jeremy D.,
Allen Mariet,
Serie Daniel J.,
Boehme Kevin L.,
Kauwe John S.K.,
Naj Adam C.,
Fardo David W.,
Dickson Dennis W.,
Montine Thomas J.,
ErtekinTaner Nilufer,
Kaeberlein Matt R.,
Crane Paul K.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.01.016
Subject(s) - caenorhabditis elegans , biology , gene , proteotoxicity , rna interference , genetics , candidate gene , computational biology , rna , protein aggregation
We sought to determine whether a systems biology approach may identify novel late‐onset Alzheimer's disease (LOAD) loci. Methods We performed gene‐wide association analyses and integrated results with human protein‐protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. Results We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1 , and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H , and APP were differentially expressed in the temporal cortex. Discussion Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.