Genetics of Glaucoma

To note: This transcript has been lightly edited for clarity.

David Hutton, Ophthalmology Times: I am David Hutton from Ophthalmology time. With me today is Dr. Janey Wiggs, Assistant Chief of Clinical Research in Ophthalmology at Massachusetts Eye & Ear, Dr. Wigs will discuss the genetics of glaucoma, a topic she presented at the recent annual meeting of the ‘American Academy of Ophthalmology. Thank you for coming today. Tell us about your presentation.

Janey Wiggs, MD, Ph.D.: The presentation I gave at the American Academy of Ophthalmology this year was intended to provide an overview of what we know about the genes and genetic mutations that can cause or contribute to glaucoma. Thus, glaucoma is best understood as an early-onset disease versus a late-onset disease, and particularly with respect to genetics.

Early forms of glaucoma are inherited as what we call Mendelian traits or autosomal recessive autosomal dominant traits. And these diseases are relatively rare in populations. They are hereditary and are caused by mutations with very significant effects. So if you have the mutation you have the disease, on the other hand it is the common forms of glaucoma like primary open angle glaucoma which are inherited because the 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 of these variants has a very small effect on overall disease risk. It is therefore only an aggregate that the threshold of the disease is reached. So what’s really been fascinating over the last decade is that we’ve been able to use this genetic information for both early-onset diseases and late-onset or common diseases, for genetic testing. And so for early disorders, we can test a panel of genes. There are about 12 genes now that we know cause these conditions. And when we find a mutation in a family, we are able to inform the genetic counseling of that family, which helps them understand the risk or additional family members.

And, and also, in some cases, can identify people for early treatment and benefit from better surveillance, so that the disease can be treated as soon as possible.

For adult diseases, there’s been really huge progress over the last couple of years and the development of polygenic risk scores. And it’s a way of, of measuring the genetic load of all the risk factors that cause these common disorders in an individual. Thus, people who have the highest genetic load for these disorders have an earlier onset of the disease, and the disease is also more severe than people who have a lower genetic load. And that gives us a really good way to stratify populations by their baseline risk of disease. And so, you know, we’re able to identify people who have the highest genetic burden as defined by these tests. And so that can benefit, again, from early monitoring and early initiation of treatment.

Another aspect of genetic research that has a significant impact on clinical glaucoma care, now and in the future, is the possibility of developing therapies based on these genetic mutations and genetic information. So there are a few genes and gene pathways for early onset diseases that may be targets, at least in preclinical studies of gene therapies, and that includes my association as well as the tech and angiopoietin signaling pathway. And then, for adult diseases, some of the pathways that we identify that may contribute to disease may also benefit from particular therapeutic approaches. For example, certain mitochondria-related proteins may contribute due to a specific type of glaucoma that would benefit from therapy to improve or restore mitochondrial function.

We are very optimistic about the future of using genetics to improve clinical outcomes for patients with glaucoma, we have work to do before we can, you know, fully realize the benefits of these approaches. For early onset disease, we only have, you know, as I said, only about 12 genes. And that means our diagnostic yield for genetic testing for these families is only about 20%. So we have to find new genes to improve that, that understanding of those tests. And we have a number of ongoing projects that do that. And we’re very excited about some recent findings that have come out 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 who are high, who carry this high genetic burden as defined by this polygenic risk score. And we also have an ongoing project in conjunction with Mount Sinai in New York, where we’re looking at our respective hospital biobanks and identifying those at high and low genetic risk, and then characterizing the clinical phenotype associated with them with those different genetic burdens. So I think there’s a bright future for genetics and glaucoma, and we’re very excited to be part of that research.

DH: Excellent. What is the next step in your research?

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

As I mentioned, we have this project where we’re actually looking at people who have these high and low genetic loads defined by the polygenic risk score, which is a very exciting opportunity to find out the disease characteristics that define these groups high genetic loads.