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Editors Selection IGR 14-2

Basic Science: IOP is not the only culprit, genome studies say

Mahantesh Biradar
Anthony Khawaja

Comment by Mahantesh Biradar & Anthony Khawaja on:

High intraocular pressure (IOP) is the most important modifiable risk factor for primary open-angle glaucoma (POAG), and recent genome-wide association studies (GWAS) have identified hundreds of genetic signals linked to IOP and glaucoma.1,2 The etiology of POAG involves both IOP-dependent and IOP-independent mechanisms,3 but GWASs focused on IOP-independent traits remain limited.

To address this issue, Huang Y and colleagues applied GWAS-by-subtraction—a genomic structural equation modelling approach—to dissect POAG into IOP-dependent and IOP-independent components. This method subtracts genetic effects from an IOP GWAS (n = 97,644) from those in a POAG GWAS (14,853 cases; 106,544 controls), separating IOP-independent genetic contributions to POAG. Seventeen independent genome-wide significant SNPs were identified for the IOP-independent component.

These components display distinct genetic associations with other traits. The IOP-independent component correlates with glaucoma endophenotypes (cup area, disc area, cup-to-disc ratio), whereas the IOP-dependent component is associated with blood pressure.

Pathway enrichment analysis identified “Apolipoprotein A-1 binding” as significantly enriched for the IOP-independent component, while “negative regulation of vascular permeability” was most enriched for the IOP-dependent component.

Single-cell and tissue enrichment analyses revealed distinct gene expression patterns: IOP-dependent genes were enriched in the juxtacanalicular region of the trabecular meshwork and retinal fibroblasts, while IOP-independent genes were enriched in photoreceptors and the visual cortex.

A genetic risk score (GRS) derived from the IOP-independent component was associated with 26 distinct retinal microvascular features, unlike the IOP-dependent GRS.

This study highlights the importance of separating POAG genetics into IOP-dependent and IOP-independent components

This study highlights the importance of separating POAG genetics into IOP-dependent and IOP-independent components, offering deeper insights into the distinct biological pathways driving disease risk. Future genetic research using similar approaches may improve our understanding of the causal mechanisms underlying normal-tension glaucoma (NTG) and enable earlier prediction through NTG-specific polygenic risk scores.

References

  1. Khawaja AP, Cooke Bailey JN, Wareham NJ, et al. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet. 2018;50(6):778-782. doi:10.1038/ s41588-018-0126-8
  2. Gharahkhani P, Jorgenson E, Hysi P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nat Commun. 2021;12(1):1258. Published 2021 Feb 24. doi:10.1038/s41467-020-20851-4
  3. Kim KE, Park KH. Update on the Prevalence, Etiology, Diagnosis, and Monitoring of Normal-Tension Glaucoma. Asia Pac J Ophthalmol (Phila). 2016;5(1):23-31. doi:10.1097/APO.0000000000000177

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