RGD Reference Report - 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.

General

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.
Authors:	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 Ertekin-Taner, Nilufer Kaeberlein, Matt R Crane, Paul K
Citation:	Mukherjee S, etal., Alzheimers Dement. 2017 Oct;13(10):1133-1142. doi: 10.1016/j.jalz.2017.01.016. Epub 2017 Feb 24.
RGD ID:	13824970
Pubmed:	PMID:28242297 (View Abstract at PubMed)
PMCID:	PMC5568992 (View Article at PubMed Central)
DOI:	DOI:10.1016/j.jalz.2017.01.016 (Journal Full-text)
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 Aß 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 Aß 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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
Alzheimer's disease	onset	IEP		13824970		RGD
Alzheimer's disease	onset	ISO	NDUFS3 (Homo sapiens)	13824970; 13824970		RGD

Objects Annotated

Genes (Rattus norvegicus)

Ndufs3 (NADH:ubiquinone oxidoreductase core subunit S3)

Genes (Mus musculus)

Ndufs3 (NADH:ubiquinone oxidoreductase core subunit S3)

Genes (Homo sapiens)

NDUFS3 (NADH:ubiquinone oxidoreductase core subunit S3)

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InterViewer (Protein-Protein Interactions) unavailable	Gviewer (Genome Viewer) unavailable	Variant Visualizer (Damaging Variants) unavailble Variant Visualizer (Damaging Variants) unavailable
InterViewer (Protein-Protein Interactions)	GViewer (Genome Viewer)	Variant Visualizer (Damaging Variants)

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MOET (Multi-Ontology Enrichement)	GOLF (Gene-Ortholog Location Finder)

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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.