Study Identifies Genetic Variants in African Ancestry Linked to Glaucoma Risk

Joan O’Brien, MD

Credit: Penn Medicine

A comprehensive multicohort genome-wide association study (GWAS) among individuals with African ancestry provided novel insight into genetic variants with pathophysiological significance for primary open-angle glaucoma (POAG), the most common form of the hereditary disease.¹

An investigative team of ophthalmologists and genetic researchers behind the GWAS detected 46 genome-wide risk loci significantly associated with glaucoma. Replication and post-GWAS analyses identified two previously undescribed variants and one previously associated variant as potentially causal for glaucoma.

A leading cause of global, irreversible blindness, glaucoma affects nearly 44 million people, with a projected prevalence of 80 million by 2040.² Individuals of African ancestry are often frequently and severely affected by the inherited disease, but the genetic structure in this population has rarely been studied.

“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,” corresponding author Joan O’Brien, MD, director of the Penn Medicine Center for Genetics of Complex Disease, explained in a statement.³ “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.”

POAG can occur when normal drainage of eye fluid is blocked and a buildup of intraocular pressure (IOP) in the eye damages the optic nerve and results in permanent vision loss.² Loss of vision generally begins in the periphery, followed by loss in the central field of vision. As the disease does not exhibit early symptoms, permanent damage has usually already occurred by the time vision loss is experienced.

The GWAS involved data and genetic samples for 11,725 individuals of African ancestry, including 6,003 cases of glaucoma and 5,272 controls, from 3 African population datasets.¹ In the study, investigators worked with Black community leaders and radio stations to promote the importance of glaucoma screening for people of African descent. Those enrolled in the GWAS were prompted with the opportunity to either enroll in or opt out of future studies.

After the GWAS and other genetic analyses, investigators identified two novel gene variants implicated in the formation of glaucoma. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated the variants rs1666698 (mapping to DBF4P2) and rs34957764 (mapping to ROCK1P1), as likely causal.

The analysis also indicated a third variant, rs11824032 (mapping to ARHGEF12), as likely causal. Previously, the variant was associated with the cup-to-disc ratio in a genetic co-localization analysis. For individuals of African ancestry, the polygenic risk score for POAG from the mega-analysis was found to outperform a much larger GWAS derived from individuals with European ancestry, suggesting the importance 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 overaffected population,” Shefali Verma, PhD, an assistant professor in pathology and laboratory medicine at the University of Pennsylvania, said in a statement.²

Based on these data, O’Brien and colleagues are aiming to develop better methods for early diagnosis of glaucoma for early treatment. The improved risk score from this analysis could benefit both screening and treatment decisions for glaucoma before it leads to vision loss.

“We are now working with community leaders to lead us in determining which other diseases over-affect this understudied population and are of greatest importance for further screening and research,” O’Brien said.² “We are also sharing our genetic database with other researchers across departments and schools that are studying diseases that over-affect African ancestry populations.”

References

1. _{A multi-cohort genome-wide association study in African ... - cell press. Cell. January 18, 2024. Accessed January 19, 2024. https://www.cell.com/cell/fulltext/S0092-8674(23)01338-7.}
2. _{CellPressNews. Study with over 11,000 individuals of African descent finds genetic variants linked to glaucoma. EurekAlert! January 18, 2024. Accessed January 19, 2024. https://www.eurekalert.org/news-releases/1031002.}
3. _{Tham, Y.C., Li, X., Wong, T.Y., Quigley, H.A., Aung, T., and Cheng, C.Y. (2014). Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121, 2081–2090}