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Genetic discovery could lead to a treatment for glaucoma blindness
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.
注释：
glaucoma: n
表示" 青光眼"，means "an eye disease that damages the optic nerve and impairs vision (sometimes progressing to blindness)"，如：Glaucoma is an important cause of blindness. 青光眼是导致眼睛失明的一个重要原因。
cataract: n
表示"白内障"，means "an eye disease that involves the clouding or opacification of the natural lens of the eye"，如：Advances in medicine have made cataracts much less worrisome. 医学的发展让白内障也不再那么可怕了。
heritable: adj
表示"可遗传的；可继承的"，如：Genetic analysis in any organism requires stable heritable differences. 在任何生物中进行遗传学分析时总是需有稳定的遗传性状的差别。
intraocular: adj
表示"眼内的"，如：This occurs as a result of various intraocular diseases such as high myopia. 这是由于各种眼内疾病如高度近视的结果。
abnormality: n
表示"异常；畸形"，means "an abnormal physical condition resulting from defective genes or developmental deficiencies"，如：The girl was scared by the man's abnormality. 这个女孩被这个男人的变态吓坏了。
drainage: n
表示" 排水；排水系统；"，如：Bad drainage caused the land to be flooded. 排水不利容易使土地淹水。
novel: adj
表示" 新奇的"，means "new and strange"，如：It's a novel experience. 那是一段新奇的经历。
stealth: n
表示" 秘密行动；偷偷摸摸;鬼祟"，如：She prefers to do good by stealth. 她喜欢秘密地为他人做好事。
peripheral: adj
表示" 外围的；不重要的"，means "on or near an edge or constituting an outer boundary; the outer area"，如：We dealt with the peripheral aspects of a cost reduction program. 我们谈到了降低成本计划的一些外围问题。
retina: n
表示" 视网膜"，如：Sight is made possible by rays of light impinging on the retina. 由于光线射到视网膜上,眼睛才看得见。
lupus: n
表示" 狼疮；天狼座", 如：Infection can cause a lupus flare.感染可导致狼疮复发。
sclerosis: n
表示" 硬化(症)"，如：Tuberous sclerosis (TSC) is a common autosomal dominant disease. 结节性硬化症是一种临床较常见的显性遗传病。
causality: n
表示" 缘由；因果关系"，means "the relation between causes and effects"，如：There is no causality between financial structure and real economy.金融结构和实体经济之间并不存在因果关系。
中文简要说明：
青光眼是一种棘手的眼病，它会导致失明，并且通常是不可逆转。目前只能降低眼压治疗，但是还无法修受损的视神经。现在科学家持续寻找与青光眼相关的基因，有一些基因相当关键，或许是治疗的线索。
2021 年，澳洲QIMR Berghofer 医学研究中心和美国哈佛医学院的跨国际研究团队，发现了 127 个与青光眼有关基因，这些基因在一定程度上解释了最常见的青光眼「原发性(遗传型)青光眼」，但仍有许多问题无法解释。
研究人员开始有史以来最大规模的全球全基因组关联研究（GWAS），寻找与眼压、视神经损伤相关的其他基因。他们的调查样本有60万名欧洲人以及280万其他各洲的受试者。这是因为青光眼发病率最高的族裔在非洲和亚洲血统，因此多血统多来源就相当重要。
这场调查发现了185 个以前未知的青光眼相关基因，总数达到312 个；而且，研究人员首次找到「保护视神经作用的基因」。
研究员马克葛雷格(Stuart MacGregor)说：「现有的治疗方法只专注于降低眼压，这相当被动。我们希望找到一种方法，让视网膜本身变得强健，能承受较大的压力，防止造成永久性失明的损伤。我们的新发现确实令人兴奋，因为这是第一次确认了一组可以在视网膜细胞中，唤起神经保护作用的基因。」
「有了这个线索之后，我们找到一些药物可以摧动这些基因，这将可预防视网膜和视神经损伤。」
该研究还发现青光眼与免疫相关疾病（包括狼疮和多发性硬化症）之间，存在显著的遗传相关性。或许治疗这些免疫疾病的现有药物，也可以治疗青光眼；当然，这需要进一步的研究，以确认因果关系。
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