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Alzheimers Dement. 2017 Oct;13(10):1133-1142. doi: 10.1016/j.jalz.2017.01.016. Epub 2017 Feb 24.

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 information

1
Department of Medicine, University of Washington, Seattle, Washington, USA. Electronic address: smukherj@uw.edu.
2
Department of Pathology, University of Washington, Seattle, Washington, USA.
3
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
4
Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, Florida, USA.
5
Department of Biology, Brigham Young University, Provo, Utah, USA; Department of Neuroscience, Brigham Young University, Provo, Utah, USA.
6
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
7
Department of Biostatistics, University of Kentucky, Lexington, Kentucky, USA.
8
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
9
Department of Medicine, University of Washington, Seattle, Washington, USA.

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.

KEYWORDS:

Alzheimer's disease; Brain expression; C. elegans; Network analysis; Protein-protein interaction; SNP; Systems biology

PMID:
28242297
PMCID:
PMC5568992
[Available on 2018-10-01]
DOI:
10.1016/j.jalz.2017.01.016
[Indexed for MEDLINE]

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