Abstract
Purpose :
Population ageing has led to an increase in the burden of disease associated with neurodegenerative disorders, with Primary Open Angle Glaucoma (POAG) and Alzheimer’s Disease (AD) being amongst the most pervasive. For POAG, the only modifiable risk factor is increased intra-ocular pressure (IOP) and lowering IOP is the target of nearly all treatment options. However, both structural and functional damage compatible with POAG diagnosis is frequently observed in the absence of elevated IOP and often patients continue to progress despite control of IOP levels. To explore non-IOP factors in POAG, we investigated a suspected shared predisposition to neurodegeneration by identifying candidate pleiotropic genes between POAG and AD.
Methods :
Utilizing eMAGMA, we derived eQTL-informed gene-level summary statistics from GWAS data for POAG and AD. We then employed a composite null hypothesis methodology, PLACO, to identify candidate pleiotropic genes. Subsequently, we assessed the POAG-specific effects of the prioritized genes through a Mendelian Randomization (MR)-based approach using two-sample MR to obtain the effect of cortex-specific gene expression on POAG risk.
Results :
We identified 5,465 genes with available gene-level summary statistics for both POAG and AD following eMAGMA annotation and ten candidate pleiotropic genes were identified through PLACO. Increased expression in the brain cortex of four genes —CRHR1, LRRC37A2, ARL17A, ANXA1 (all OR=1.001; p<0.001)— showed elevated risk of POAG. Several of the prioritized genes are contained within the haplotype containing MAPT, a neurodegenerative disease-associated gene which encodes protein tau. PLEKHM1 and KANSL1 are involved in biological processes such as protein degradation and mitophagy, critical for neuronal function. ANXA11 has a role in vesicular trafficking and is associated with amyotrophic lateral sclerosis.
Conclusions :
By leveraging a joint analysis between POAG and AD, this work contributes to explaining some of the unaccounted variation in POAG disease risk and progression. Further studies on the prioritized genes may elucidate insights into neurodegeneration and contribute to novel screening, diagnostic, classification, and therapeutic targeting. Our results may also report on pathogenic mechanisms of particular importance or patient subgroups underserved by current care paradigms.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.