@article {8558, title = {Systems biology approach to late-onset Alzheimer{\textquoteright}s disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.}, journal = {Alzheimers Dement}, volume = {13}, year = {2017}, month = {2017 Oct}, pages = {1133-1142}, abstract = {

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer{\textquoteright}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.

}, keywords = {Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Animals, Genetically Modified, Antigens, Neoplasm, Caenorhabditis elegans, Disease Models, Animal, Early Growth Response Protein 1, Female, Gene Expression Regulation, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Male, Membrane Transport Proteins, Mitochondrial ADP, ATP Translocases, NADH Dehydrogenase, Polymorphism, Single Nucleotide, Protein Interaction Maps, RNA Interference, Systems Biology, Temporal Lobe}, issn = {1552-5279}, doi = {10.1016/j.jalz.2017.01.016}, author = {Mukherjee, Shubhabrata and Russell, Joshua C and Carr, Daniel T and Burgess, Jeremy D and Allen, Mariet and Serie, Daniel J and Boehme, Kevin L and Kauwe, John S K and Naj, Adam C and Fardo, David W and Dickson, Dennis W and Montine, Thomas J and Ertekin-Taner, Nilufer and Kaeberlein, Matt R and Crane, Paul K} }