NEW YORK – A team led by researchers at the University of Pennsylvania has tracked down new genetic contributors to a common form of glaucoma known as primary open-angle glaucoma (POAG), a heritable vision loss condition that involves optic nerve damage stemming from eye pressure produced by obstructed fluid drainage. POAG is particularly prevalent in individuals of African ancestry, and the study focused on this population.
"Our work is an important step toward achieving future goals, including defining subgroups of disease that aid in early detection, providing the capability for early screening within families, and discovering targetable pathways for personalized therapeutic interventions," co-senior and corresponding author Joan O'Brien, director of the University of Pennsylvania's Penn Medicine Center for Genetics of Complex Disease, and her colleagues wrote in a study published in Cell on Thursday.
With a genome-wide association study that included 6,003 individuals with POAG and 5,272 unaffected control individuals, both of African ancestry, researchers from the University of Pennsylvania, the New York Genome Center, and elsewhere focused in on 353 SNPs at 46 loci with genome-wide significant ties to POAG. They validated those associations with data for more than 43,500 additional cases and controls from four research cohorts.
"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," O'Brien said in a statement, explaining that African ancestry individuals are roughly five times as likely to experience glaucoma, with 15-fold the risk of related vision loss or blindness compared to their European ancestry counterparts.
"POAG is the leading cause of irreversible blindness in the world today, and familial blindness perpetuates increased morbidity, poverty, and mortality across generations," she and her co-authors explained in the paper. "The lack of genetic studies in the most affected African ancestry population is both a failure of science and a failure of our moral obligation to address systemic racism prevalently visible today."
After a series of functionally informed fine-mapping, co-localization, and in silico analyses, together with cell line experiments, the team highlighted a potentially causal variant in the ARHGEF12 gene, along with previously unappreciated associations involving SNPs in the ROCK1P1 and DBF4P2 genes.
Using POAG risk variants obtained with genetic data across African ancestry individuals, meanwhile, the researchers put together a polygenic risk score (PRS) that outperformed a PRS containing European ancestry risk variants in an analysis that included 26,100 African ancestry individuals from three cohorts.
"Although more experimental evidence is ultimately required to pinpoint causal mechanisms and generate predictive tools for early screening of POAG, many useful insights can be drawn from our study," the authors wrote. "Future studies can also help to determine whether African ancestry individuals have different responses to treatments, such as recently approved ROCK inhibitors."