DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Alzheimer's disease. The EFO term Alzheimers disease was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: Alzheimers disease

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

E Pérez-Palma, BI Bustos, CF Villamán, MA Alarcón, ME Avila, GD Ugarte, AE Reyes, C Opazo, GV De Ferrari

TITLE:

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

JOURNAL:

PloS one None 2014, Vol 9, pp. e95413

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<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. PUBMED: 24755620
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