RNA interference

Biology

Gene

Protein aggregation

Proteotoxicity

Genetics

Candidate gene

Computational biology

Caenorhabditis elegans

Alzheimer s & Dementia

Introduction 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 cor...

Systems biology approach to late‐onset Alzheimer's disease genome‐wide association study identifies novel candidate genes validated using brain expression data and <i>Caenorhabditis elegans</i> experiments

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