Study of more than 11,000 individuals of African descent finds genetic variants linked to glaucoma

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One of the leading causes of irreversible blindness around the world, glaucoma affecting up to 44 million people. Although people of African ancestry are most frequently and severely affected by this hereditary disease, there has been little research done in the genetic roots of the disease among this population.

Researchers now are unwrapping results that show previously unknown inherited genetic variants that contribute to primary open-angle glaucoma (POAG), the most common form of the disease. The study was based on the analysis of 11,275 individuals of African descent and is being published January 18, 2024, in Cell.¹

Corresponding author Joan O’Brien, MD, the director of the Penn Medicine Center for Genetics of Complex Disease, who was funded by a $17.9 million grant from the National Institutes of Health for this research, noted the research has demonstrated how the disease impacts the demographic.

“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,” she said in the news release. “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.”

In a news release, O’Brien pointed out the research was driven by 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.2

According to the study, POAG can happen in a patient when the normal drainage of eye fluid becomes blocked, leading to a buildup of pressure within the eye. If the intraocular pressure rises too much, it can damage the optic nerve and result in permanent vision loss. Patients diagnosed with POAG can experience a loss of peripheral vision first, followed by loss in the central field of vision.

There are no early warning signs of the disease, and by the time a patient is experiencing vision loss, permanent damage usually has already occurred.

“Elevated intraocular pressure is currently the only targetable component of the disease, but many patients maintain normal pressure levels or do not respond to pressure-lowering therapies,” co-author Rebecca Salowe, MSE, Research Project Manager at UPenn, said in the news release. “This suggested to us that POAG has additional underlying mechanisms that could be elucidated by genetic studies.”

Discovery of known and previously undescribed loci from the discovery mega-analysis of African ancestry individuals. (Image credit:Cell/Verma et al)

According to the study, researchers worked with community leaders in the African community to organize glaucoma screenings in churches and senior centers. The researchers worked with WURD Radio, a Black-owned station, on a campaign promoting the importance of glaucoma screening in the community. The screenings were offered free of change, and participants were provided with a free lunch regardless of whether they agreed to participate in the study or not.

Ultimately, the researchers were able to pull together data and genetic samples for 11,275 people (6,003 individuals with glaucoma and 5,272 controls). Importantly, the participants were given the opportunity to either enroll in or opt out of future studies.

Using genome-wide association studies and other forms of genetic analysis, the team identified two novel gene variants implicated in the formation of glaucoma. These variants were rs1666698, which is tied to the gene DBF4P2, and rs34957764, which is linked to the gene ROCK1P1.¹

According to the study, researchers identified a third variant, rs11824032, which is tied to ARHGEF12. Tey noted the variant was previously linked with cup-to-disc ratio, a measure of glaucoma severity, in a genetic co-localization analysis.

The researchers examined their findings and compared them with results primarily featuring people of European descent, they found these variants were more common in people of African ancestry.

Shefali Verma, PhD, an assistant professor in pathology and laboratory medicine at UPenn, pointed out in the news release this work highlights the essential role of diversity in genetic research.

“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,” she said in the news release.

Moreover, the researchers were able to validate results in the Penn Medicine BioBank, an in-house repository of genetic information linked to health records. It includes a particularly diverse collection of genetic material.

Marylyn Ritchie, PhD, director of the Institute for Biomedical Informatics at UPenn, noted the importance of the validation.

“To enhance our work, we were able to identify patients in the Penn Medicine BioBank with glaucoma and controls to validate the genetic effects we gleaned from the initial cohort we analyzed,” Ritchie said. “Without that resource, it would have been much more difficult to produce such strong work.”

The researchers are now focusing on better methods for diagnosing glaucoma early, when it’s most amenable to treatment. Using key variants, researchers came up with a polygenic risk score that exceeded a similar risk score developed using information from individuals of European ancestry. This improved risk score is anticipated to help patients make decisions about screening and treatment for glaucoma before it produces vision loss.

O’Brien pointed out that researchers are now working with community leaders to lead them in determining which other diseases over-affect this understudied population and are of greatest importance for further screening and research.

“We are also sharing our genetic database with other researchers across departments and schools that are studying diseases that over-affect African ancestry populations,” she concluded. “These collaborations are resulting in much more research on the health of a population that has been historically understudied.”

References:

1. Joan, O’Brien, Shefali S. Verma, Harini V. Gudiseva, Vnkata R.M. Chavali, et.al; A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma. Cell. Published January 18, 2024. Accessed January 19, 2024. Volume 187. Issue 2. DOI: 10.1016/j.cell.2023.12.006.

2. Study with over 11,000 individuals of African descent finds genetic variants linked to glaucoma. EurekAlert! Accessed January 19, 2024. https://www.eurekalert.org/news-releases/1031002