Mega-analysis identifies gene variants associated with glaucoma in people of African ancestry

PHILADELPHIA— A new analysis focusing specifically on people of African ancestry identified three gene variants that may be contributing to this population’s susceptibility to developing and being blinded by glaucoma. People of African ancestry are five times as likely as others to develop glaucoma and up to 15 times as likely to be blinded by the condition, but the vast majority of research has used data from people of European ancestry. Led by researchers at the Perelman School of Medicine at the University of Pennsylvania, the study was published today in Cell.

“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,” said study author Rebecca Salowe, MSE, a research project manager in the lab of senior author Joan O’Brien, MD, a professor of Ophthalmology and director of the Penn Center for Genetics of Complex Disease.

Involving more than 11,200 people of African ancestry, the new study uncovered two particular variants that correlated with primary open-angle glaucoma, the most common form of glaucoma, which is the leading cause of irreversible blindness worldwide. The variants discovered in the analysis were rs1666698, tied to the gene DBF4P2, and rs34957764, linked to ROCK1P1.

In addition to identifying these two variants as “likely causal” of glaucoma, a third variant was also identified (rs11824032 tied to ARHGEF12), which was associated with cup-to-disc ratio, a measure of glaucoma severity.

The majority of previously associated variants identified in other ancestral populations did not replicate in these African ancestry subjects, which could be tied to the genetic differences that occur in these different groups.

As of 2019, only two percent of all genome-wide association studies—analyses of entire genomes to find commonalities that correlate to disease or other traits—have been conducted in individuals whose ancestry is tied to Africa. The study, led by first author Shefali Setia Verma, PhD, an assistant professor in Pathology and Laboratory Medicine, Salowe, O’Brien, and Marylyn Ritchie, PhD, a professor of Genetics and director of the Institute of Biomedical Informatics, sought to work toward addressing that disparity while also looking into a condition that disproportionately affects individuals of African ancestry. It’s also an issue Penn Medicine has worked toward for decades, utilizing wide community-focused screenings that this new research could help to inform.

"This work highlights the essential role of diversity in genetic research,” Verma said. “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 primary open-angle glaucoma in this overaffected population."

A particular advantage that the researchers had in this study was the ability to validate their results in the Penn Medicine BioBank, an in-house repository of genetic information linked to health records. It features a particularly diverse collection of genetic material.

“To enhance our work, we were able to identify patients in the Penn Medicine BioBank with glaucoma 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.”

With the variants the researchers identified, a polygenic risk score—a measure of disease risk due to an individual’s genes—was developed that outperformed a similar risk score generated with information from an analysis of individuals of European ancestry. Having this improved risk score in hand could help patients make decisions about screening and treatment for glaucoma before it becomes a blinding illness.

“We are sharing our genetic database with other researchers across departments and schools that are studying diseases that over-affect African-ancestry populations,” O’Brien said. “These collaborations are resulting in much more research on the health of an historically understudied population.”

O’Brien also explained her team is currently doing research to discover how exactly these genes contribute to disease risk and severity.

However, with knowledge of the variants now in hand, the researchers hope to influence clinical approaches to glaucoma in this population and work toward reversing inequities that have persisted for many years.

“Glaucoma is a highly familial disease, so premature and irreversible vision loss can affect multiple family members, contributing both to adverse health and economic outcomes,” Salowe said. “With current treatments for glaucoma having limited success, there is an urgent need for large genetic studies to identify novel targets for screening and therapeutic intervention in African ancestry individuals.”

This research was funded primarily by the National Eye Institute (1R01EY023557-5701) and the Vision Research Core Grant (P30 EY001583).