Abstract
Purpose :
A growing number of studies have suggested common pathological pathways between Alzheimer’s disease (AD) and age-related macular degeneration (AMD) as evidenced by the progressive accumulation of proinflammatory protein, amyloid β (Aβ), in plaques of the AD brain and the drusen of AMD retina. To explore the shared genomic profile between AD and AMD, a bioinformatic pipeline approach was adapted to analyze disease related PheWAS datasets via an interaction predictor database followed by a pathways database.
Methods :
Data were collected from the UKBioBank PheWAS datasets (AD: 430 cases and 400600 controls, and AMD: 2180 cases and 395156 controls). Top loci variants were identified as the single genetic variant with a minor allele frequency (MAF) range of 5e-5≤MAF<0.50. Genes corresponding to top loci variants were identified based on the single genetic variant proximity to nearest gene. PheWAS candidate genes were analyzed through the STRING database as 3 different groups, 1) AD only, 2) AMD only, and 3) AD+AMD. Within each group sub-clusters corresponding to a string of protein interactions were identified and further analyzed through the REACTOME pathway database (pathways p-value ≤ 0.05).
Results :
STRING analysis revealed minimal protein-protein interaction enrichment (PPI-E) in the AD only group (p-value: 1) and the AMD only group (p-value: 0.072), while the AD+AMD group demonstrated significant PPI-E (p-value: 0.044). REACTOME pathway analysis demonstrated 3 shared pathways unique to the AD+AMD group: 1) glucagon signaling pathway (p-value: 0.024), 2) activation of GABA receptors (p-value: 0.018) and 3) aquaporin mediated transport (p-value: 0.033).
Conclusions :
The application of an integrated bioinformatic analysis enabled us to identify three dominant pathways demonstrating the association between AD and AMD. Specifically, glucagon secretion has been shown to be regulated by activation of GABA receptors via an Akt-dependent manner. Glucagon has also been documented to increase the expression of aquaporin. Our findings highlight the convergence of AD and AMD pathologic pathways in the dysregulation of aquaporin with its potential contribution to defective Aβ secretion that may lead to Aβ accumulation in both AD and AMD.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.