1. 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
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Mukherjee S, Russell JC, Carr DT, Burgess JD, Allen M, Serie DJ, Boehme KL, Kauwe JSK, Naj AC, Fardo DW, Dickson DW, Montine TJ, Ertekin-Taner N, Kaeberlein MR, and Crane PK
- Subjects
- Alzheimer Disease chemically induced, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Animals, Genetically Modified, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Caenorhabditis elegans genetics, Disease Models, Animal, Early Growth Response Protein 1 genetics, Early Growth Response Protein 1 metabolism, Female, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Heparin-binding EGF-like Growth Factor genetics, Heparin-binding EGF-like Growth Factor metabolism, Humans, Male, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Mitochondrial ADP, ATP Translocases genetics, Mitochondrial ADP, ATP Translocases metabolism, NADH Dehydrogenase genetics, NADH Dehydrogenase metabolism, Protein Interaction Maps, RNA Interference physiology, Alzheimer Disease genetics, Alzheimer Disease pathology, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics, Systems Biology, Temporal Lobe metabolism
- Abstract
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 cortex., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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