ICYMI: Genetics of glaucoma

Note: This transcript has been lightly edited for clarity.

David Hutton, Ophthalmology Times: I'm David Hutton of Ophthalmology Times. Joining me today is Dr. Janey Wiggs, associate chief of Ophthalmology clinical research at Massachusetts Eye & Ear, Dr. Wigs will discuss genetics of glaucoma, a topic she presented at the recent American Academy of Ophthalmology annual meeting. Thank you for joining us today. Tell us about your presentation.

Janey Wiggs, MD, PhD: The presentation that I made at the American Academy of Ophthalmology this year was to provide an overview of what we know about genes and gene mutations that can cause or contribute to glaucoma. So, glaucoma is best understood as early onset disease versus late onset disease, and especially with regard to genetics.

Early onset forms of glaucoma are inherited as what we call Mendelian traits or autosomal, dominant autosomal recessive traits. And these diseases are relatively rare in populations. They do run in families, and they're caused by mutations with very large effects. So if you have the mutation you have the disease, in contrast, are the common forms of glaucoma like primary open angle glaucoma, which are inherited as complex traits are polygenic traits. And there are many genetic variants or risk factors that can contribute to these types of glaucoma.

But individually, each one of these variants has a very small effect on overall disease risk. So it's only an aggregate that the disease threshold is reached. So what's really been fascinating over the past decade or so, is that we've been able to use this genetic information for both early onset disease and late on or common disease, for genetic testing. And so for early onset disorders, we can test for a panel of genes. There's about 12 genes now that we know cause these conditions. And when we find a mutation in a family, we're able to inform the genetic counseling for that family, which helps them understand risk or additional family members.

And, and also, in some cases, can identify people for early treatment and benefit from improved surveillance, so that the disease can be treated at the earliest possible stages.

For adult onset diseases, there have been really tremendous advances in the last couple of years and the development of polygenic risk scores. And this is a way of, of measuring the genetic burden of all the risk factors that cause these common disorders in an individual person. And so people who have the highest genetic burden for these disorders have earlier onset of disease and the disease is also more severe than people who have lower genetic burden. And this gives us a really great way to stratify populations according to their basic risk of disease. And so, you know, we're able to identify those people who have the highest genetic burden as defined by these tests. And that can therefore benefit from, again, early surveillance and early initiation of treatment.

Another aspect of the genetic research that's very much impacting glaucoma clinical care, and now and very much so in the future is the opportunity to develop therapies that are based on these genetic in this these gene mutations and genetic information. So there's a couple of genes and gene pathways for early onset disease that can be targets, at least in preclinical studies of gene based therapies, and this includes my association and also the tech and angiopoietin one signaling pathway. And then for the adult onset diseases, some of the pathways that we're identifying that may contribute to disease may also benefit from particular therapeutic approaches. For example, there are some mitochondria related proteins that that may contribute due to a specific type of glaucoma that would benefit from therapy to improve or restore mitochondrial function.

We're very optimistic about the future of using genetics to improve clinical outcomes for glaucoma patients, we have some work to do before we can, you know, fully realize the benefit of these approaches. For the early onset disease, we have, you know, as I said, only about 12 genes. And that means that our diagnostic yield for genetic testing for these families is only about 20%. So we need to discover new genes to improve that, that comprehension of that testing. And we have a number of projects underway that are doing that. And we're very excited about a couple of recent discoveries that have been published using exome sequencing where we've identified mutations and EFMP. One in some families and also thrombospondin, one in some other families.

So, in addition, there's work that we need to do to understand some of the clinical outcomes of people that are high, that are carriers of this high genetic burden as defined by that polygenic risk score. And we also have a project underway in collaboration with Mount Sinai in New York, where we're looking at our respective hospital biobanks and identifying people with high and low genetic risk and then characterizing the clinical phenotype that's associated with these with these differences in genetic burdens. So I think that there's a bright future for genetics and glaucoma, and we're very excited about being involved in this research.

DH: Excellent. What's the next step for your research?

JW: Well, the next step for the early onset forms is to continue our whole exome. And we're doing actually whole genome sequencing and a number of families this is we have a NIH grant, to do this in collaboration with our Australian colleagues. And we are using that approach to find new causality for the early onset forms, and the adult onset forms.

As I mentioned, we have this project where we're actually examining people who have these high and low genetic burden defined by the polygenic risk score, which is a very exciting opportunity to discover features of the disease that that are defining these high genetic burden groups.