Home caregiver and senior woman holding hands
Home caregiver and senior woman holding hands

A genome-wide association study (GWAS) has revealed several genetic variants linked with glaucoma among people with African ancestry.

People of African descent have a five-fold increased risk of this leading cause of irreversible blindness compared with those from European backgrounds.

The researchers have used their findings to create a polygenic risk score that outperforms current options and could help with screening and treatment options for the condition.

Their study is published in the journal Cell.

“Our current treatments for this blinding disease are inadequate, and precision medicine could be applied if we more clearly understood the full pathophysiology of this inherited neurodegeneration” said corresponding author Joan O’Brien, PhD, director of the Penn Medicine Center for genetics of complex disease.

Co-author Rebecca Salowe, PhD, who works in O’Brien’s lab, added: “Our work is an important step toward defining subgroups of glaucoma, providing the capability for early screening, and discovering targetable pathways for personalized therapeutic interventions.”

Primary open-angle glaucoma (POAG) is the most common form of the condition and occurs when normal fluid drainage in the eye becomes blocked, leading to a build-up of pressure.

Discovery of known and previously undescribed loci from the discovery mega-analysis of African ancestry individuals. [Cell/Verma et al].
This intraocular pressure can damage the optic nerve resulting in vision loss and is currently the only targetable component of the disease, said Salowe.

As many patients maintain normal pressure and do not respond to  pressure-lowering therapies, additional underlying genetic mechanisms may be at work.

The researchers therefore conducted a mega-analysis for POAG in people of African ancestry, which included three datasets and a total of 11,275 individuals.

Significant findings were then further investigated through replication studies in four independent datasets, functional validation studies, and in silico analysis.

The team also compared the genetic architecture of POAG in African and non-African ancestry populations.

The research revealed 46 risk loci associated with the condition, of which only two were previously reported in glaucoma studies.

The team identified two genetic variants linked with the POAG, one of which was the variant rs1666698 linked with the DBF4 zinc-finger pseudogene 2 (DBF4P2).

The other variant rs34957764 was linked with the Rho-associated coiled-coil-containing protein kinase 1 pseudogene 1 (ROCK1P1) gene region.

Rho-associated coiled-coil kinase, a pseudo gene resulting from partial duplication of the ROCK1gene, regulates cellular responses such as cell growth, proliferation, and apoptosis.

A third variant rs11824032 linked with the gene ARHGEF12 was also identified, which had previously been associated with the glaucoma severity measure of cup-to-disc ratio in a genetic colocalization analysis.

The team used the findings to develop a polygenic risk score that outperformed another based on people with European ancestry. This could help patients make decisions about screening and treatment for glaucoma before it produces vision loss.

O’Brien and co-workers suggest that future studies could help determine whether people of African ancestry have different responses to treatments, such as recently approved ROCK inhibitors.

They conclude: “POAG is the leading cause of irreversible blindness in the world today, and familial blindness perpetuates increased morbidity, poverty, and mortality across generations.

“The lack of genetic studies in the most affected African ancestry population is both a failure of science and a failure  of our moral obligation to address systemic racism prevalently visible today.”

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