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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.

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.
Pubmed: (View Article at PubMed) PMID:28242297
DOI: Full-text: DOI:10.1016/j.jalz.2017.01.016

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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CRRD Object Information
CRRD ID: 13824970
Created: 2018-11-09
Species: All species
Last Modified: 2018-11-09
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.