The Genetics of Glaucoma

There has been a remarkable expansion in understanding of the genetic underpinnings of the major forms of glaucoma. As research progresses, we hope to learn much more.

Glaucoma is the term used for a group of diseases that irreversibly damage the optic nerve, leading to vision loss and ultimately, if untreated, blindness. Genetic factors are considered to play a key role in all major forms of glaucoma.

In recent years the curtain that has blocked our view of the genetic cause of glaucoma has begun to lift, ushering in a new era in our understanding of the fundamental causes of glaucoma.

Primary open-angle glaucoma (POAG) is the most common type of glaucoma and has no obvious abnormality in the eye that points to a cause. Although mutations in several genes, including myocilin, optineurin, and CYP1B1, have been reported to cause POAG, these genes account for less than 10% of cases worldwide. In the past 2 years, large scale genetic studies that have examined the blood samples of thousands of glaucoma patients have been instrumental in the discovery of more common genetic risk factors for POAG. A risk factor is something that doesn’t always lead to a condition but increases the risk of having that condition. For glaucoma, these genetic factors include changes in the DNA sequences (near or in the genes such as caveolin 1 and 2 (CAV1/CAV2), CDKN2B antisense RNA, TMCO1, SIX1/SIX6, and LRP12/ZFPM2 genes) or actual loss of DNA (TBK1 and GALC), and several different genes have been implicated. How these genes cause or influence the likelihood of developing POAG is of major interest.

Glaucoma is often thought of as a disease of middle age or older adults. However there are many inherited forms of glaucoma that affect young children. Primary congenital glaucoma (PCG) is the most common childhood glaucoma affecting children from birth to age 3 and is a major cause of blindness in this young population. Mutations in the CYP1B1 gene have been found to cause PCG in children worldwide and are the dominant genetic cause for glaucoma in children in the Middle East and central Europe. In the United States only 15% of children with PCG have a mutation in CYP1B1, so there are ongoing efforts to identify additional causes in these young patients. Other types of glaucoma related to maldevelopment of the eye occur in older children – the genes implicated in these forms of glaucoma play a key role in the development of the eye, so when they malfunction they cause abnormalities in the eye’s fluid drainage system which leads to elevated eye pressures and glaucoma. The genes currently known to be associated with these forms of glaucoma include PITX2, PITX3, FOXC1, FOXE3, PAX6, LMX1B, and MAF.

Primary angle-closure glaucoma (PACG) is the second most common form of glaucoma and affects over 16 million people globally. In this form of glaucoma the drainage angle closes over time, blocking the pathway to the drainage system and causing high eye pressures. Very recently a large scale genetics study identified genetic variants that are associated with this form of glaucoma. These variants are in or near PLEKHA7, PCMTD1/ST18, and COL11A1. How these genes contribute to this form of glaucoma is not clear.

Exfoliation glaucoma (XFG), also called pseudoexfoliation glaucoma, affects millions and is the most common identifiable form of open-angle glaucoma in the world. XFG results from exfoliation syndrome, a common condition characterized by the deposit of white protein-like material that forms on the lens and within the fluid drainage system of the eye, as well as tissues throughout the body. Genetic variants of LOXL1 and CNTNAP2 genes have been associated with XFG. Researchers are currently working on how these genes contribute to the formation of these protein deposits and how these cause glaucoma.

In summary, there has been a remarkable expansion of our understanding of the genetic underpinnings of the major forms of glaucoma. At the moment these advances in our knowledge are tantalizing since these genetic discoveries are not yet at the stage that they can be put to practical use. We still don’t quite understand how these gene abnormalities actually cause glaucoma, However, as research progresses, these discoveries hold the promise that we will soon know much more about the mechanisms by which glaucoma occurs and we will hopefully begin to develop treatments that may be specific to each of the different mechanisms of glaucoma caused by these different gene abnormalities.


Article by Yutao Liu, MD, PhD. Last reviewed on March 22, 2022.

Yutao Liu, MD, PhD

Yutao Liu, MD, PhD

Yutao Liu, MD, PhD is an Adjunct Assistant Professor at Duke University School of Medicine in the Departments of Medicine and Ophthalmology and the Director of Duke University Molecular Genomics Core facility in Durham, North Carolina.