The State of the Art of Glaucoma Genetics

The State of the Art of Glaucoma Genetics

SAN FRANCISCO – Advances in glaucoma genetics potentially hold the key to new therapies for prevention, early detection, and a cure, researcher Janey L. Wiggs, MD, PhD, said in an update on glaucoma genetics in her keynote at the Glaucoma Research Foundation’s 2019 Glaucoma 360 New Horizons Forum here.

The goal of glaucoma genetics research, Dr. Wiggs said, “is to identify genes that define biological pathways that cause the disease and therefore could be targets of potentially curative and preventative therapies.”

Glaucoma will affect 80 million people worldwide by 2020, and that number will only increase as the population ages, Dr. Wiggs said. Because of this, the need to develop curative and preventative treatments is even more urgent. Dr. Wiggs is associate chief, ophthalmology clinical research, and associate director, Howe Laboratory at Massachusetts Eye and Ear in Boston.

Identifying Genetic Culprits

Early onset forms of glaucoma are caused by rare gene mutations. Researchers identify those mutations through genetic linkage studies and now, more commonly, next-generation sequencing approaches.

People with the more common adult-onset glaucoma share common genetic risk factors with relatively small effects when compared with early-onset glaucoma. “It’s only in aggregate, when you have [multiple] genetic risk factors, perhaps in combination with environmental risk factors, that the disease becomes manifest,” Dr. Wiggs explained.

The challenge in trying to find these small-effect genes is the need for very large sample sizes to produce a statistically significant result. To get these large numbers, Dr. Wiggs and other researchers formed the NEIGHBORHOOD Consortium in 2012 to better understand the genomic architecture of glaucoma. The initiative is supported by the National Eye Institute and includes 47 investigators across the US. It has collected data on more than 5,000 cases, published more than 40 papers to date, and has identified a number of genes that contribute to early-onset glaucoma or contribute to adult-onset glaucoma.

More Genes Needed

Myocilin (MYOC) is the first gene implicated in glaucoma. Mutations cause some forms of juvenile and adult-onset primary open-angle glaucoma. An approach using CRISPR-Cas9-mediated genome editing to remove mutant MYOC proteins has been shown to lower intraocular pressure (IOP). Researchers out of the University of Iowa published a study on this breakthrough in 2017.1

Research has focused on the role of the Tec gene in the impairment of the endothelial angiopoietin (ANG)-TIE pathway, which has been implicated in glaucoma and vascular disease, as well as tumor growth and spread. “It’s become clear in the last few years that rare Tec mutations cause a congenital glaucoma and juvenile glaucoma,” said Dr. Wiggs. “We’ve also shown that rare mutations of [ANG1] can cause congenital and adult glaucoma. We’ve recently learned common variants in ANG1 and ANG2 are associated with elevated intraocular pressure by interfering with Schlemm’s canal formation or function. Restoring Tec signaling could reduce intraocular pressure.”

Mutations in CAV1, ABCA1, and ARHGEF12 interact with each other to affect cholesterol efflux; the cholesterol pathway is associated with open-angle glaucoma. Statins, which inhibit the pathway, could reduce primary open-angle glaucoma risk, Dr. Wiggs said.

In a study published in June 2018, researchers – including Dr. Wiggs, NEIGHBORHOOD, and the UK Biobank Eye and Vision Consortium – identified 68 new loci associated with IOP.2

Yet, Dr. Wiggs said researchers still need more genes. “Compared to other complex disorders, glaucoma is lagging behind in terms of the number of genetic elements we know contribute to disease,” she said. Dr. Wiggs also stressed the importance of further early-onset glaucoma research, the need for more animal models that can more rapidly screen genetic defects, and the addition of a genetic component to clinical trials.

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  1. Jain A, Zode G, Kasetti RB, et al. CRISPR-Cas9-based treatment of myocilin-associated glaucoma. Proc Natl Acad Sci U S A. 2017;114:11199-204.
  2. Khawaja AP, Cooke Bailey JN, Wareham NJ, et al, for the UK Biobank Eye and Vision Consortium and NEIGHBORHOOD Consortium. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet. 2018;50:778-82.