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    Gene Variants Linked to Glaucoma

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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

    Fundus photographs show a healthy control eye and an eye with large cup-to-disc ratio

    FUNDUSCOPIC VIEWS. Fundus photographs of a healthy control eye (1A and 1B) and an eye with large cup-to-disc ratio (2A and 2B).

    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


    1 Verma SS et al. Cell. 2024;187:464-480.

    2 Mamidipaka A et al. Genes. 2023;14(9):1809.


    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.

    Disclosure Category



    Consultant/Advisor C Consultant fee, paid advisory boards, or fees for attending a meeting.
    Employee E Hired to work for compensation or received a W2 from a company.
    Employee, executive role EE Hired to work in an executive role for compensation or received a W2 from a company.
    Owner of company EO Ownership or controlling interest in a company, other than stock.
    Independent contractor I Contracted work, including contracted research.
    Lecture fees/Speakers bureau L Lecture fees or honoraria, travel fees or reimbursements when speaking at the invitation of a commercial company.
    Patents/Royalty P Beneficiary of patents and/or royalties for intellectual property.
    Equity/Stock/Stock options holder, private corporation PS Equity ownership, stock and/or stock options in privately owned firms, excluding mutual funds.
    Grant support S Grant support or other financial support from all sources, including research support from government agencies (e.g., NIH), foundations, device manufacturers, and\or pharmaceutical companies. Research funding should be disclosed by the principal or named investigator even if your institution receives the grant and manages the funds.
    Stock options, public or private corporation SO Stock options in a public or private company.
    Equity/Stock holder, public corporation US Equity ownership or stock in publicly traded firms, excluding mutual funds (listed on the stock exchange).


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