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A new analysis that focuses on individuals of African ancestry identified three gene variants that may be linked to why people of African descent are disproportionately affected by and blinded by glaucoma.1 The study aimed to identify variants of pathophysiological importance to primary open-angle glaucoma (POAG) in individuals of African ancestry in order to gain in-sight into the genetics of the disease, said corresponding author Joan O’Brien, MD, Professor of Ophthalmology and Director of the Penn Center for Genetics of Complex Disease at the University of Pennsylvania Perelman School of Medicine in Philadelphia.
People of African ancestry are five times as likely as people of other ancestries to develop glaucoma and up to 15 times as likely to be blinded by it.2
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FUNDUSCOPIC VIEWS. Fundus photographs of a healthy control eye (1A and 1B) and an eye with large cup-to-disc ratio (2A and 2B).
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Study details. The genome-wide association study published in Cell analyzed data from three African data-sets that included 11,275 individuals—6,003 people with POAG and 5,272 controls. To conduct the analysis, the scientists used functionally informed fine-mapping, multiple trait co-localization, and in silico validation—experimental techniques performed via computer—to pinpoint the three genes.
“We detected 46 risk loci associated with POAG at genome-wide significance,” Dr. O’Brien said, explaining that they then identified “two previously undescribed” gene variants: rs1666698, associated with gene DBF4P2, and rs34957764, which is tied to the ROCK1P1 gene. Additionally, they spotlighted one previously associated variant, rs11824032, linked to the ARHGEF12 gene, which is related to cup-to-disc ratio.
Study significance. Any work that expands glaucoma research to include genetic analysis “is critical to understanding how high-risk populations are disproportionately affected by this blinding condition,” said Carla Siegfried, MD, the Jacquelyn E. and Allan E. Kolker, MD, Distinguished Professor of Ophthalmology and Visual Sciences and Vice Chair for Diversity, Equity, and Professionalism at Washington University in St. Louis.
Because glaucoma is heritable, affecting families across generations and perpetuating associated morbidity and mortality, Dr. O’Brien said research must be inclusive, noting that most POAG research has relied on data from people of European ancestry.
“Only 2% of genetic studies have been conducted in individuals of African ancestry,” she said. “We developed a polygenic risk score that was more predictive of disease risk than a polygenic risk score derived from a much larger predominantly European population.”
Polygenic risk scores are important because they provide a measure of disease risk due to one’s genes, said Dr. Siegfried. “Identifying risk loci within the whole genome associated with glaucoma risk is very exciting and enhances polygenic risk score analysis,” she said.
Study limitations. While this may be the largest African ancestry genome-wide association study for POAG, it does not compare in size to similar studies using datasets of European ancestry individuals.
Next steps. “We are performing further studies using structural genomics, functional genomics, and transcriptomics to make these variants—and others that we discover using orthogonal platforms for analysis—robust,” Dr. O’Brien said. “We will then develop a genetic test that identifies disease risk.”
Identifying the genetics of heritable diseases in the populations that are most acutely affected will better enhance screening, diagnosis, and therapeutics development, she said, adding, “This is an unmet medical need because we do not understand glaucoma’s pathophysiology, and many affected individuals see disease progression despite currently available treatments.”
The scientific community hasn’t often focused on population diversity in both genetic research and clinical trials, and scientists are only beginning to examine disparities in cellular physiology from subjects of different ancestral backgrounds, said Dr. Siegfried. The new findings—of risk variants in specific genes associated with tissue genetics—may help lead to further understanding of glaucoma pathophysiology and cellular function in trabecular meshwork and/or retinal ganglion cells, and she said, that “is even more exciting.”
—Brian Mastroianni
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1 Verma SS et al. Cell. 2024;187:464-480.
2 Mamidipaka A et al. Genes. 2023;14(9):1809.
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Relevant financial disclosures—Dr. O’Brien: None; Dr. Siegfried: None.
For full disclosures and the disclosure key, see below.
Full Financial Disclosures
Dr. Schocket—None.
Dr. Wolf— None.
Dr. O’Brien—Atheneum Partners: C; Calico: C; Cerner Enviza (includes Kantar Health): C; Life Biosciences: C.
Dr. Siegfried—NEI: S.
Dr. Fekrat—Alcon: P; Bausch Surgical: C; Genentech: S; Glaukos: C; Optos: S.
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