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Glaucoma GWAS Meta-Analysis Uncovers New Risk Loci, Shared Risk Across Ancestry Groups

NEW YORK – A team from the US and Australia has tracked down dozens of new glaucoma risk loci in individuals from European, Asian, and African ancestry groups, while getting a better sense of the overlap between the parts of the genome contributing to risk of the heritable blindness-causing diseases in different populations.

"The number of genes identified will lead to the discovery of new biological pathways that can lead to glaucoma, and in turn, new targets for therapeutics," co-senior author Janey Wiggs, associate chief of ophthalmology clinical research at Massachusetts Eye and Ear, codirector of Harvard Medical School's Glaucoma Center of Excellence, and associate director of the center's Ocular Genomics Institute, said in a statement.

For a paper published in Nature Communications on Wednesday, the researchers reported on findings from a primary open angle glaucoma (POAG) genome-wide association meta-analysis that included nearly 34,200 individuals with the disease and more than 349,300 unaffected controls. Their search highlighted 83 loci with known ties to glaucoma risk, along with 44 glaucoma-associated loci that had not previously been linked to the eye condition.

"[T]his study identified a strong cross-ancestry genetic correlation for POAG between Europeans, Asians, and Africans, and identified 127 genome-wide significant loci by combining GWAS results across these ancestries," the authors wrote, adding that "cross-ancestry genetic data improved fine-mapping of causal variants."

In an email, Wiggs noted that the newly detected loci "provide critical data for development of polygenic risk scores and other methods to detect disease at early stages. This is particularly important for glaucoma as treatment should be initiated before onset of irreversible damage to the optic nerve, an early disease stage that is not evident to the patient."

For their analyses, the investigators considered array-based genotyping profiles for 34,179 individuals with POAG and 349,321 controls over four meta-analysis stages focused on participants from European, Asian, or African populations alone and together. Their results pointed to "broadly consistent" effects for most of the new or known POAG-associated loci in individuals from the three ancestry groups, suggesting that genetic testing for the eye condition may be applied more broadly.

Although prior studies on the genetics of glaucoma have largely focused on participants with European ancestry, rates of the progressive optic nerve degeneration disease tend to be particularly high in individuals from African and Asian populations, first author Puya Gharahkhani, a statistical genetics researcher at the QIMR Berghofer Medical Research Institute, explained in a statement.

Results from past studies suggest that genetic testing may help to find individuals "would benefit from sight-saving early monitoring or treatment," Gharahkhani said, though "we weren't sure until now that the genetic indicators were true for people of different ancestries."

Along with fine-mapping focused on potential causal variants at each POAG-associated locus, the team went on to search for sex-specific variants linked to POAG, as well as potential treatment targets and biological pathways enriched for POAG-associated variants.

"By integrating multiple lines of genetic evidence," the authors concluded, "we implicate previously unknown biological processes that might contribute to glaucoma pathogenesis, including intracellular chloride channels, adipose metabolism, and YAP/HIPPO signaling."