All over the world, glaucoma is a serious disease that can lead to irreversible blindness. In Singapore, it causes 60% of adult blindness in the Chinese population. Now, several large collaborations anchored by NUS Medicine researchers are helping to figure out the genes involved in this potentially devastating disease.

In the normal eye, fluid is constantly flowing into the front part of the eye and draining out through a narrow “sieve” of tissue. In glaucoma, this drainage is disturbed, causing fluid to accumulate in the front part of the eye. The fluid buildup increases pressure in the eye, which can damage the optic nerve and eventually lead to blindness.

The disease has 3 main forms: open-angle glaucoma, angle-closure glaucoma, and exfoliation glaucoma. In open-angle glaucoma, the most common form in the world, the angle between the iris and cornea is normal and wide. However, the channels through which fluid drains from the eye gradually become blocked, bringing on symptoms over time. In angle-closure glaucoma, the iris-cornea angle is unusually narrow, making it more difficult for fluid to drain from the eye. Pressure can build up quickly, causing sudden symptoms that require immediate medical attention. Exfoliation glaucoma develops from exfoliation syndrome (XFS), in which materials slough off the lens and iris, blocking the eye’s drainage channels.

The risk of having any type of glaucoma increases with age and if a family member has glaucoma. For example, people whose siblings or parents have glaucoma are three times more likely to have glaucoma than those with no family history of the disease. This is a clue that genetic factors are involved in glaucoma.

Scientists are now starting to figure out the specific genetic factors involved in each type of glaucoma, with NUHS researchers at the forefront of this exciting work. Professor Aung Tin of the Department of Ophthalmology is either the first or last author on a series of Nature Genetics papers describing new genes linked to different types of glaucoma.

By studying many Asian and European populations, Prof Aung, with Dr Chiea-Chuen Khor from the Genome Institute of Singapore, and collaborators discovered the second ever gene to be linked to XFS (Aung, et al. 2015). This gene is important for calcium transport, which is involved in many body processes. The study groups have now expanded to include over 8000 patients, with 4 more new genes identified (unpublished findings).

Another collaboration led by Prof Aung and team found three new genes that are linked to an increased risk for PACG. Although PACG is more common in Asians than in Europeans, the genes are linked to the disease across 9 different Asian, European, and Middle Eastern patient groups.

In primary open-angle glaucoma (POAG), Prof Aung and colleagues found three new genes that are linked to both POAG and high eye pressure, a treatable risk factor for POAG. Again, the links were verified in multiple patient groups of different ethnicities.

As more genes are identified, they add to the jigsaw puzzle that is the genetic basis of glaucoma. The genes could be used in screening for glaucoma and as targets for specific glaucoma treatments.

References

1. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC. Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey. Arch Ophthalmol. 1994;112:69-73.
2. Aung T, Ozaki M, Mizoguchi T, et al. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet. 2015;47:387-392.
3. Vithana EN, Khor C-C, Quao Chunyan, et al. Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma. Nat Genet. 2012;44:1142-1147.
4. Hysi PG, Cheng C-Y, Springelkamp H, et al. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat Genet. 2014;46:1126-1132.