Genetic Discovery Could Lead to a Treatment for Glaucoma Blindness

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The largest-ever global genetic study of glaucoma has uncovered more genes associated with the disease, including never-before-identified genes that could be targeted to prevent the optic nerve damage that leads to irreversible blindness.

After cataracts, glaucoma is the second leading cause of blindness and is usually irreversible. It’s also a highly heritable disease, meaning that genetics contribute far more to the disease than environmental factors do.

Glaucoma causes progressive degeneration of the optic nerve, eventually leading to blindness. One of the major risk factors for glaucoma is eye (intraocular) pressure, where an abnormality in the eye’s drainage system causes a build-up of fluid, leading to excessive pressure and damage to the optic nerve. The symptoms can start slowly, so they may not be noticed initially. Around half of all glaucoma cases aren’t diagnosed until permanent optic nerve damage has occurred, making early detection and treatment vital.

A 2021 international study led by researchers at Australia’s QIMR Berghofer Medical Research and Harvard Medical School in the US identified 127 genes that increase a person’s risk of developing glaucoma. Now, QIMR Berghofer has led further research into the genetics of glaucoma, identifying hundreds of novel genes, including some that may offer a new way of treating the disease.

“Glaucoma robs your sight by stealth,” said Stuart MacGregor, one of the study’s co-authors. “You lose your peripheral vision first, and then one eye often covers for the loss of sight in the other. You don’t realize what’s happening until you’ve already suffered permanent damage and loss of vision.”

The 127 previously identified genes went some way to explaining the heritability of the most common form of glaucoma, primary open-angle glaucoma, but left much still unexplained. So the researchers went seeking more answers, undertaking the largest-ever global genome-wide association study (GWAS) looking for additional genes linked to intraocular pressure and optic nerve damage.

They first conducted a GWAS using more than 600,000 participants of European ancestry before they moved on to an unprecedented study of over 2.8 million subjects from multiple ancestries. The researchers considered that taking a multi-ancestry approach was important, given that glaucoma rates are highest in people of African and Asian ancestry.

“The global nature of our data allowed us to identify a large number of glaucoma risk genes, and to also discover that most of those genes are actually shared across different ethnic ancestry groups,” said Puya Gharahkhani, another co-author. “This means that genetic tests for glaucoma are likely to work well across a wide range of ancestries.”

The researchers’ large-scale study uncovered 185 previously unknown genes linked to glaucoma risk, more than doubling the number of genes identified in the 2021 study and bringing the total number to 312. And, for the first time, the researchers were able to identify genes that had a role in protecting the optic nerve.

“Existing treatments focus only on lowering eye pressure,” MacGregor said. “The dream has always been to find a way to make the retina itself stronger so it can withstand the build-up of pressure and prevent the damage that causes permanent blindness. Our findings are really exciting because for the first time we’ve discovered a set of genes that could be targeted to induce this ‘neuro-protection’ in the retinal cells.”

Up until now, existing drug treatments have targeted intraocular pressure. Along with the researchers’ identification of genes related to optic nerve damage independent of raised eye pressure, they’ve identified potential medications that have already been proven safe in humans.

“We’ve also identified existing drugs that could be used on those genetic targets,” said MacGregor. “This could rapidly advance effective treatment to finally prevent retina and optic nerve damage.”

The study also uncovered a significant genetic correlation between glaucoma and immune-related diseases, including lupus and multiple sclerosis. Further research is needed to confirm the causality of these genes, which may lead to the repurposing of existing drugs used to treat these immune disorders for the treatment of glaucoma.

“Glaucoma is one of the most strongly genetic of all human diseases,” Gharahkhani said. “We can use our genetic discoveries to identify those who are at higher risk. If we can find people before the disease develops, we can prevent blindness in those people.”

The study was published in the journal Nature Genetics, and in the below video, produced by QIMR Berghofer, the researchers speak about their research and its implications.

Source: QIMR Berghofer

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