Large Multi-Ethnic Study Identifies More Than 100 Variants Linked to Glaucoma

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Man having an eye exam at ophthalmologist's office

A large multi-ethnic genome wide association study has identified 44 new variants associated with primary open-angle glaucoma and confirmed 83 that were already known.

The study was an international collaboration, led by researchers at QIMR Berghofer Medical Research Institute in Brisbane and Harvard Medical School, and included 34,179 people with primary open-angle glaucoma (POAG) and 349,321 controls.

Notably, to improve accuracy and applicability 6935 glaucoma cases and 39,588 controls in the cohort were of Asian descent and 3281 glaucoma cases and 2791 controls had African ancestry – something that has often been neglected in earlier studies.

“Previous observational studies have shown that individuals of African ancestry, followed by Latinos and Asians, have higher POAG disease burden compared to those with European ancestry, suggesting important differences in genetic risk and highlighting the need to compare the genetic architecture of these ethnic groups,” write Puya Gharahkhani, Ph.D., associate professor at QIMR Berghofer Medical Research Institute in Australia, and colleagues in the journal Nature Communications.

POAG is the leading cause of irreversible blindness around the world and is caused by progressive degeneration of the optic nerve and intraocular pressure. Treatments can slow progression, but it is often diagnosed too late for them to have a meaningful effect.

There are many gene variants that increase a person’s risk of developing this type of glaucoma, which are often inherited. Although many gene variants have already been identified, more information is needed to help assess risk more effectively and also to help develop more personalized therapies for this disease.

“These new findings come out of the highest-powered genome-wide association study of glaucoma to date,” said co-senior study author Janey Wiggs, M.D., Ph.D., a professor at Harvard Medical School. “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.”

Rates of glaucoma are higher in populations of Asian or African descent, but most genome wide association studies have been carried out in populations with European ancestry. This study allowed the researchers to compare genetic variation across different ancestry groups.

Overall, 44 new areas of POAG risk variation (loci) in the genome were identified and 83 loci identified in earlier studies were confirmed. Several genes were identified as having a particular contribution to disease development in patients with POAG including SVEP1, RERE, VCAM1, ZNF638CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6.

The researchers found that most POAG-associated mutations have similar effects in all ancestry groups. However, one newly identified variant in the IQGAP1 gene was significantly associated with risk for POAG in people of African ancestry, but not in those of European or Asian descent.

Having accurate genetic data for people of multiple different ancestries is important for creating the most accurate polygenic risk scores. These tests are a way of adding up different genetic variants and assessing how they impact your risk for developing a specific disease. For something like POAG this is important as although a cure has yet to be found, early treatment can slow disease progression and allow people to keep their sight for longer.

“Glaucoma rates are highest in African and Asian ancestry groups, but the largest genetic studies of glaucoma in the past focused on people of European ancestry,” said Gharahkhani.

“Those studies showed genetic tests could be used to help identify who would benefit from sight-saving early monitoring or treatment, but because of the narrow scope of the genetic data, we weren’t sure until now that the genetic indicators were true for people of different ancestries.”

The research team are also hoping their findings will help new treatments for POAG to be developed, perhaps targeting causative genes.

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