Overrepresentation of glutamate signaling in Alzheimer's disease: Network-based pathway enrichment using meta-analysis of genome-wide association studies

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

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

37 Citas (Scopus)

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 genewise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent genebased 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<2.7×10-11, p<1.9×10-11; GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly overrepresented (p<5.1×10-8) 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.

Idioma originalInglés
Número de artículoe95413
PublicaciónPLoS ONE
Volumen9
N.º4
DOI
EstadoPublicada - 22 abr 2014

Áreas temáticas de ASJC Scopus

  • Bioquímica, genética y biología molecular (todo)
  • Agricultura y biología (todo)
  • General

Huella

Profundice en los temas de investigación de 'Overrepresentation of glutamate signaling in Alzheimer's disease: Network-based pathway enrichment using meta-analysis of genome-wide association studies'. En conjunto forman una huella única.

Citar esto