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Overrepresentation of Glutamate Signaling in Alzheimer's Disease: Network-Based Pathway Enrichment Using Meta-Analysis of Genome-Wide Association Studies

Author

Listed:
  • Eduardo Pérez-Palma
  • Bernabé I Bustos
  • Camilo F Villamán
  • Marcelo A Alarcón
  • Miguel E Avila
  • Giorgia D Ugarte
  • Ariel E Reyes
  • Carlos Opazo
  • Giancarlo V De Ferrari
  • the Alzheimer's Disease Neuroimaging Initiative
  • the NIA-LOAD/NCRAD Family Study Group

Abstract

Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer's disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p

Suggested Citation

  • Eduardo Pérez-Palma & Bernabé I Bustos & Camilo F Villamán & Marcelo A Alarcón & Miguel E Avila & Giorgia D Ugarte & Ariel E Reyes & Carlos Opazo & Giancarlo V De Ferrari & the Alzheimer's Disease Neu, 2014. "Overrepresentation of Glutamate Signaling in Alzheimer's Disease: Network-Based Pathway Enrichment Using Meta-Analysis of Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 9(4), pages 1-16, April.
    • Handle: RePEc:plo:pone00:0095413
    DOI: 10.1371/journal.pone.0095413
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    References listed on IDEAS

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    1. Xiaolan Hu & Eve Pickering & Yingxue Cathy Liu & Stephanie Hall & Helene Fournier & Elyse Katz & Bryan Dechairo & Sally John & Paul Van Eerdewegh & Holly Soares & the Alzheimer's Disease Neuroimaging , 2011. "Meta-Analysis for Genome-Wide Association Study Identifies Multiple Variants at the BIN1 Locus Associated with Late-Onset Alzheimer's Disease," PLOS ONE, Public Library of Science, vol. 6(2), pages 1-9, February.
    2. David Moher & Alessandro Liberati & Jennifer Tetzlaff & Douglas G Altman & The PRISMA Group, 2009. "Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement," PLOS Medicine, Public Library of Science, vol. 6(7), pages 1-6, July.
    3. Gregory S Barsh & Gregory P Copenhaver & Greg Gibson & Scott M Williams, 2012. "Guidelines for Genome-Wide Association Studies," PLOS Genetics, Public Library of Science, vol. 8(7), pages 1-2, July.
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