Overrepresentation of glutamate signaling in alzheimer's disease: Network-based pathway enrichment using meta-analysis of genome-wide association studies
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Fecha
2014-04
Profesor/a Guía
Facultad/escuela
Idioma
en
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Public Library of Science
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Licencia CC
Atribution 4.0 International (CC BY 4.0)
Licencia CC
https://creativecommons.org/licenses/by/4.0/deed.es
Resumen
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,2.7610211, p,
1.9610211; GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly
overrepresented (p,5.161028
) in the Alzheimer’s disease Neuroimaging Initiative (ADNI) study, which was used as a
targeted replication sample. Interestingly, components of the glutamate signaling SNs are coordinately expressed in
disease-related tissues, which are tightly related to known pathological hallmarks of AD. Our findings suggest that genetic
variation within glutamate signaling contributes to the remaining genetic risk of AD and support the notion that functional
biological networks should be targeted in future therapies aimed to prevent or treat this devastating neurological disorder.
Notas
Indexación: Scopus
Palabras clave
Glutamate, Alzheimer's Disease, Metaanalysis, Gene Ontologies, Genome-Wide Association Studies, Single Nucleotide Polymorphisms, Synapses, Genetics of Disease
Citación
PLoS ONE. Volume 9, Issue 4. 22 April 2014. Article number e95413
DOI
DOI: 10.1371/journal.pone.0095413