Study with 11,275 people of African descent finds genetic variants linked to glaucoma

Glaucoma is the leading cause of irreversible blindness around the globe, 

affecting up to 44 million people. Although people of African ancestry are most frequently and severely affected by this hereditary disease, its genetic underpinnings in this population have rarely been studied. Now, previously unknown inherited genetic variants that contribute to primary open-angle glaucoma (POAG) have been discovered. The study was funded by the National Institutes of Health (NIH) and published January 18, 2024, in Cell.

“Individuals with African ancestry are five times more likely to be affected by glaucoma and up to 15 times more likely to experience vision loss or blindness from the disease compared to individuals with European ancestry,” says corresponding author Joan O’Brien, MD, Director of the Penn Medicine Center for Genetics of Complex Disease. “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.”  She explains that this research was made possible thanks to key contributions from glaucoma specialists of African ancestry and other Black community leaders living in the Philadelphia area, who were able to boost enrollment in the research because of increased trust within the community. Scientists from fields including genetics, ophthalmology, and computational biology also made important contributions to the paper. POAG, a common form of glaucoma, can occur when normal drainage of eye fluid becomes blocked, leading to a buildup of pressure within the eye. If this IOP rises too much, it can damage the optic nerve and result in permanent vision loss. People with POAG generally have a loss of peripheral (side) vision first, followed by loss in the central field of vision. Unfortunately, the disease has no early symptoms, and by the time vision loss is noticed, permanent damage usually has already occurred. Elevated IOP is currently the only treatable component of the disease, but many patients maintain normal pressure levels or do not respond to pressure-lowering therapies, said co-author Rebecca Salowe, MSE, Research Project Manager at UPenn. “This suggested to us that POAG has additional underlying mechanisms that could be elucidated by genetic studies.” 

The researchers worked with Black community leaders to organize glaucoma screenings in churches and senior centers. They also worked with a Black-owned radio station (WURD Radio) on a campaign promoting the importance of glaucoma screening in the Black community. The screenings were free, and participants got a free lunch whether or not they agreed to enroll in the study. The investigators collected data and genetic samples for 11,275 people (6,003 with glaucoma and 5,272 controls).

Using genome-wide association studies and other forms of genetic analysis, the team identified two novel gene variants implicated in the formation of glaucoma, one tied to the DBF4P2 gene and another tied to the ROCK1P1 gene. A third variant tied to ARHGEF12 was also found. It was previously associated with cup-to-disc ratio, a measure of glaucoma severity. When comparing their findings to results primarily featuring people of European descent, the team found these variants were more common in people of African ancestry. 

“This work highlights the essential role of diversity in genetic research,” says Shefali Verma, PhD, an assistant professor in pathology and laboratory medicine at UPenn. “Without our focus on this specific ancestry group, these unique and critical insights might have remained lost, and we would not have been able to substantially enhance our understanding of the genetics behind POAG in this over affected population.” 

The team is currently focused on developing better methods for diagnosing glaucoma early, when it’s most amenable to treatment. Using identified variants, they developed a polygenic risk score that outperformed a similar risk score resulting from information from people of European ancestry. This improved risk score could help patients make decisions about screening and treatment for glaucoma before it produces vision loss. “We are now working with community leaders to lead us in determining which other diseases over-affect this understudied population… We are also sharing our genetic database with other researchers across departments and schools that are studying diseases that over-affect African ancestry populations. These collaborations are resulting in much more research on the health of a population that has been historically understudied.”

Source: Cell Press, ScienceDaily, January 18, 2024; see source article