Researchers ‘Strike Gold’ with Discovery of New Gene Variations Associated with Glaucoma

This research was supported by BrightFocus

Thanks to the mammoth worldwide effort to collect genetic information on glaucoma patients, there’s been a major breakthrough with the discovery of several new gene variants associated with the most common form of glaucoma. Together three new studies have more than doubled the number of gene variants associated with the disease, and lend hope that genetic screening can be used to identify and direct treatment for people at greatest risk of losing their sight.

BrightFocus is a direct sponsor of research contributing to two of the studies, which were reported in an advance online edition of Nature Genetics on August 31. BrightFocus 2008-10 grantee Jamie Craig, PhD, is senior author and co-led an Australian study that identified variants of three genes as having a significant association with primary open-angle glaucoma (POAG)—the most common type and a major cause of blindness worldwide. Craig is associated with the South Australian Health and Medical Research Institute and is an associate professor at the Flinders University Centre for Ophthalmology and Eye Vision Research in Bedford Park, South Australia, near Adelaide.

BrightFocus also funded parts of the research in a second study, also co-authored by Craig and several other Australian study researchers. It identifies new genetic variations influencing intraocular pressure and susceptibility to glaucoma in individuals of multiple ancestry.

The third study was conducted in China and is unique for being the first large-scale study of POAG in an Asian population. It associated variants near two genes with glaucoma risk in people from China and Singapore.

Importantly, one of the gene associations found in the Australian study was confirmed in the other two studies, lending strength to that finding.

What’s A GWAS, and How Did They Lead To These Findings?

People whose close relatives have POAG have a greater risk of developing the disease themselves. However, no single genetic mutation is responsible for POAG. Instead, the disease is “multifactorial,” meaning it stems from a combination of factors that include age, race, and other stress on the eye, in addition to individual genetic predisposition.

Thus, the objective of a genome-wide association study (GWAS), such as these, is to look at genes that have been associated with the disease in the past—either POAG or other forms of glaucoma—and then look for subtle variations in the “coding,” or chemical makeup, of those genes that exists between people with and without the disease. In research jargon, these variations are known as “single-nucleotide polymorphisms,” or SNPs.

In the Australian study, the discoveries by Craig et al came from comparing genetic information from a cohort of 1,555 patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma with that of 1,992 normal controls. Once the research team had identified possible SNPs associated with POAG, the findings were cross-checked with genetic data from two other study cohorts in Australia and two in the United States, altogether comprising more than 10,000 patients. The combined data showed the SNPs (sometimes referred to as “loci”) to be located near or within the three genes—ABCA1, AFAP1, and GMDS—all of which are expressed within the human retina, optic nerve, and trabecular meshwork.

The large amounts of data shared in the meta-analysis were drawn from investigators worldwide who collaborated on the study. In addition to Craig, additional BrightFocus-funded researchers who are co-authors include: 2013-15 grantee Alex W. Hewitt, PhD, of the Centre for Eye Research Australia and the  University of Melbourne; 2005-07 and 2014-16 grantee David Mackey, MD, of Lions Eye Institute in Nedlands, Australia; and Janie Wiggs, PhD, who is co-investigator on a BrightFocus’ 2014-2016 grant to Baojian Fan, MD, PhD, of Harvard’s Massachusetts Eye and Ear Infirmary, where they are both based.

The Australian study was also supported in part through a 2010-13 BrightFocus grant to Yutao Liu, MD, PhD, of Duke University.  

BrightFocus Vice President of Scientific Affairs Guy Eakin, PhD, characterized the results as a “huge win” in the glaucoma field. “Clearly, the investment we’ve made in these individual scientists is paying off in innovative, collaborative research,” he said.

In addition, hearing that one of the principal genes associated with glaucoma is ABCA1 “has particular resonance for us,” Eakin said, because ABCA1 “has long been understood to be genetically associated with Alzheimer’s disease” —another area of research that BrightFocus supports.

Other Studies Confirm ABAC1 and Discover Additional Genes

Lending to the excitement, the two other GWAS reported in the same issue of Nature Genetics independently discovered that gene sequence variations of the ABCA1 gene contribute to glaucoma.

"It's rock solid that this is an important result because it has been found in three different ways," Craig said in an interview with ABC Science News. "All the papers were done in different populations with different strategies and all identified the same gene.”

The ABCA1 gene is involved in the regulation of cellular cholesterol and lipid metabolism, and the exact way in which its genetic variants contribute to POAG and other forms of glaucoma has yet to be explained. “It has been shown to be involved in eye pressure in normal people and tells us for sure it is contributing to glaucoma at least partly through intraocular pressure pathways,” Craig said. However, he cautioned that it could take several years of experiments before the pathway, or disease mechanism, is known, and treatment strategies can be developed.

Initially, it’s likely that findings from all three studies will be used to develop “risk profiles” for people diagnosed with glaucoma. This will help clinicians and patients reach an informed decision about whether the disease should be treated aggressively at an earlier stage in order to preserve sight.

However, making use of the findings in this way will also take additional research. As Craig explained, “we are looking at ways to add up a genetic risk profile. If you've got a larger load of these variant genes, your risk is high.” As he indicated, additional research is required before it will be possible to apply these new findings in this way—but with these latest discoveries, the goal draws closer.