Mining Big Data for Novel Glaucoma Genes

Glaucoma and data analytics specialist Joshua Stein, M.D., M.S., and ocular geneticist Lev Prasov, M.D., Ph.D. share a 2023 Dr. David L. Epstein Award from the Association for Research in Vision and Ophthalmology (ARVO) Foundation for Eye Research.

The award recognizes a senior investigator distinguished in both glaucoma research and scientific mentorship (the mentor, Dr. Stein), and an early-career investigator (the mentee, Dr. Prasov), and is designated for a collaborative project between the two.

Drs. Prasov and Stein will partner on a proposal that combines Big Data analytics with familial studies to define novel glaucoma genes.

The origins of the project date back several years. “Dr. Stein and I first became acquainted with a family of patients with glaucoma when I was still a medical student,” Dr. Prasov recalls. “About a dozen family members suffered from normal tension glaucoma that responded poorly to traditional therapies to lower interocular pressure (IOP).” To better characterize their disease and look for a genetic root cause, whole genome and exome sequencing was performed on that group, and about 50 extended family members underwent eye examinations and deep phenotyping.

Those analyses yielded a promising lead on a genetic mutation. But proving a gene/disease association is a high bar; more work is needed to characterize the mutation, and identify the same mutation and disease profile in other patients and families. This award will help fund those crucial next steps.

“More lab studies will validate the mutation and document its functional effects,” explains Dr. Prasov. “Along with data from the initial family, we now have data from a second family.” William Pressley II, a Ph.D. candidate in genetics and genomics in the Prasov lab, will spearhead this component.

To hunt for ‘the ‘needle in a haystack,’ Dr. Stein and Dr Prasov will use Big Data analytics to sift through highly detailed information from a large cohort of glaucoma patients, including, but not limited to Kellogg patients.

Their haystack: the Sight Outcomes Research Collaborative, or SOURCE, a database of information collected by a consortium of U.S. academic ophthalmology programs for use in members’ research. Dr. Stein is Principal Investigator and Chief Data Officer of SOURCE, which is housed at U-M.

Drs. Stein and Prasov will flag patients with the same type of glaucoma, whose diseases are also unresponsive to IOP-lowering therapy. They will look at disease characteristics that track with those seen in the families, factors like corneal thickness and stiffness, and a particular pattern of visual field loss.

The group identified will provide DNA samples for gene sequencing, looking for the suspected mutation and any risk factors associated with it or other genes.

The goal is to establish whether one or more genetic mutations are the root cause of this type of glaucoma, and whether other factors shared by these patients distinguish them from other people with glaucoma.

Header image caption: Joshua Stein, M.D., M.S., Lev Prasov, M.D., Ph.D.