January 26, 2016

Glaucoma-related genes revealed

At a Glance

  • A genomic analysis identified 3 genes that contribute to the most common type of glaucoma, raising the total number to 15.
  • The findings give insights into the underlying disease mechanisms and suggest new targets for preventative therapies.
Close-up of an eye The causes of primary open angle glaucoma, the most common type of glaucoma, remain poorly understood. mishooo/iStock/Thinkstock

Glaucoma is a group of conditions that damage the optic nerve, the bundle of nerve fibers connecting the eye to the brain. It affects side vision first and often goes unnoticed for years. Glaucoma is the most common culprit behind irreversible vision loss. It affects about 2.7 million Americans and 60 million people worldwide. If detected early, vision loss can often be prevented with surgery or eye drops.

Glaucoma is most often caused by a buildup of pressure inside the eye. In primary open angle glaucoma, the most common type of glaucoma, fluid drains too slowly from a space in the front of the eye called the anterior chamber. The underlying causes of primary open angle glaucoma remain poorly understood, but likely involve both genetic and environmental influences.

To find genetic factors associated with primary open angle glaucoma, a research team led by Dr. Janey Wiggs of Harvard Medical School compared the genomes of more than 3,800 people of European ancestry who had primary open-angle glaucoma to a similar group of more than 33,000 people without it. The study was supported by NIH’s National Eye Institute (NEI). To ensure uniformity among the datasets, the researchers restricted their analysis to gene variants included in the 1000 Genomes Project reference panel, an NIH-supported catalog of human genetic variability. Results appeared online on January 11, 2016, in Nature Genetics.

The researchers found specific variations in the genes FOXC1, TXNRD2, and ATXN2 that are associated with glaucoma. Additional analyses of datasets from Europe, Australia/New Zealand, and Singapore also showed associations between glaucoma and these variants. All 3 genes are expressed in the eye. TXNRD2 and ATXN2 are active in the optic nerve.

Scientists had already identified an association between FOXC1 and glaucoma, but only in rare cases of severe early-onset glaucoma.

The TXNRD2 gene codes for an enzyme that protects against oxidative stress—the buildup of toxic byproducts from metabolism. Scientists had suspected that oxidative stress might contribute to the degeneration of the optic nerve, but until now lacked evidence.

Little is known about ATXN2. Mutations of the gene are implicated in a rare disorder called spinocerebellar ataxia 2 that causes loss of balance and coordination. Interestingly, ATXN2 is the third gene found to be associated with both glaucoma and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. However, there’s no evidence that people with glaucoma are at greater risk of developing ALS.

“This unprecedented analysis provides the most comprehensive genetic profile of glaucoma to date,” says NEI Director Dr. Paul A. Sieving. “These findings open avenues for the pursuit of new strategies to screen for, prevent, and treat glaucoma.”

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References: Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Bailey JN, Loomis SJ, Kang JH, Allingham RR, Gharahkhani P, Khor CC, Burdon KP, Aschard H, Chasman DI, Igo RP Jr, Hysi PG, Glastonbury CA, Ashley-Koch A, Brilliant M, Brown AA, Budenz DL, Buil A, Cheng CY, Choi H, Christen WG, Curhan G, De Vivo I, Fingert JH, Foster PJ, Fuchs C, Gaasterland D, Gaasterland T, Hewitt AW, Hu F, Hunter DJ, Khawaja AP, Lee RK, Li Z, Lichter PR, Mackey DA, McGuffin P, Mitchell P, Moroi SE, Perera SA, Pepper KW, Qi Q, Realini T, Richards JE, Ridker PM, Rimm E, Ritch R, Ritchie M, Schuman JS, Scott WK, Singh K, Sit AJ, Song YE, Tamimi RM, Topouzis F, Viswanathan AC, Verma SS, Vollrath D, Wang JJ, Weisschuh N, Wissinger B, Wollstein G, Wong TY, Yaspan BL, Zack DJ, Zhang K, Study EE; ANZRAG Consortium, Weinreb RN, Pericak-Vance MA, Small K, Hammond CJ, Aung T, Liu Y, Vithana EN, MacGregor S, Craig JE, Kraft P, Howell G, Hauser MA, Pasquale LR, Haines JL, Wiggs JL. Nat Genet. 2016 Jan 11. doi: 10.1038/ng.3482. [Epub ahead of print]. PMID: 26752265.

Funding: NIH’s National Eye Institute (NEI); Royal Australian and New Zealand College of Ophthalmology Eye Foundation; National Health and Medical Research Council of Australia; UK Medical Research Council; Cancer Research UK; Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases; Wellcome Trust; National Institute for Health Research; Fight for Sight; Biomedical Research Council; and Singapore National Research Foundation.