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

Shubhabrata Mukherjee, Joshua C. Russell, Daniel T. Carr, Jeremy D. Burgess, Mariet Allen, Daniel J. Serie, Kevin L. Boehme, John S.K. Kauwe, Adam C. Naj, David W. Fardo, Dennis W. Dickson, Thomas J. Montine, Nilufer Ertekin-Taner, Matt R. Kaeberlein, Paul K. Crane

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1133-1142
Number of pages10
JournalAlzheimer's and Dementia
Volume13
Issue number10
DOIs
StatePublished - Oct 2017

Keywords

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

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Mukherjee, S., Russell, J. C., Carr, D. T., Burgess, J. D., Allen, M., Serie, D. J., Boehme, K. L., Kauwe, J. S. K., Naj, A. C., Fardo, D. W., Dickson, D. W., Montine, T. J., Ertekin-Taner, N., Kaeberlein, M. R., & Crane, P. K. (2017). 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. Alzheimer's and Dementia, 13(10), 1133-1142. https://doi.org/10.1016/j.jalz.2017.01.016