CWRU PhD Candidate Andrea Waksmunski co-leads research revealing a new gene associated with age-related macular degeneration

A team of Case Western Reserve University researchers has identified a new gene associated with advanced age-related macular degeneration (AMD), the leading cause of blindness in the elderly, impacting nearly 170 million people world-wide. This gene (PLCG2, phospholipase C gamma 2) had not been previously associated with AMD and like many newly-identified genes in this disease, could potentially serve as a target for existing and new therapeutics. PhD candidate Andrea Waksmunski was first author on this work.

Jessica Cooke Bailey, PhD, MA and Jonathan Haines, PhD, jointly sponsored and supervised the study. Cooke Bailey is an assistant professor in the Department of Population and Quantitative Health Sciences, in CWRU’s School of Medicine. Haines is Chair of the department and an internationally recognized researcher in the genetics of diseases of aging including AMD and Alzheimer’s. Also on the research team and members of the Department of Population and Quantitative Health Sciences: Robert (Rob) Igo, PhD, assistant professor; Michelle Grunin, PhD, postdoctoral fellow; and Tyler Kinzy, MS, biostatistician.

Waksmunski presented the findings at the 2019 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting in Vancouver, BC; this work was published recently in the ARVO journal, Investigative Ophthalmology & Visual Science. Read more here.

For the study, Waksmunski and the CWRU team analyzed genetic data generated by the International AMD Genomics Consortium, which is led by Haines, and is considered one of the world’s largest available datasets on advanced AMD that describes associations between changes in the human genome and AMD.

“Our findings grew out of earlier research that identified several genetic loci that correlate to AMD,” said Waksmunski. “What is new in this study is that we went back to the data to look beyond those loci to identify additional genetic variations that also are implicated, despite not quite attaining initial study significance. Like many diseases with complex genetic correlations, finding all the variables, including those that may present at lower levels of statistical significance, helps clarify the complex genetic underpinnings for the disease.”

Waksmunski identified one gene (PLCG2) that was consistently associated with advanced AMD. It was found in multiple biological pathways, pointing to a role in the complex collection of genetic variations found in AMD.

“These findings further clarify the genetic architecture of the disease,” said Haines. “By looking beyond the genetic variations that stand out on their own as loci of interest, we begin to see the secondary players in this architecture that may play an influencing role, along with external environmental or behavioral factors in disease onset and progression.”

The researchers compared four genetic pathway databases including more than 14,000 pathways and 16,000 genes. They found that this gene (PLCG2) was consistently involved, which suggests that it too might be biologically important for advanced AMD, in addition to loci earlier discovered.

Existing research shows that the enzyme encoded by this gene is involved in a pathway already targeted by drugs treating wet AMD, another form of AMD. The CWRU team anticipates that their results could lead to further research about how those treatments might be developed to target the enzyme encoded by this gene (PLCG2) in patients with AMD.

Waksmunski is a PhD candidate in the Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine in Cleveland, Ohio. She anticipates defending her PhD thesis in Spring 2020. Haines is her PhD mentor; he also has an appointment in the Department of Genetics and Genome Sciences. Faculty from both departments collaborate in research drawing on huge international genomic databases to uncover correlations between diseases and genetic variations that may lead to therapeutic targets for treatments or cures.

“This is an excellent example of team science,” said Cooke Bailey. “At CWRU we create space for PhD candidates to take a lead role in discovery so they gain a sense of the science, as well as the dynamics of team work, which is so essential in research based on massive data sets around conditions that have multiple and interrelated genetic factors. Andrea Waksmunski is a promising, up-and-coming investigator who has contributed significantly to further uncovering the architecture of a disease that, as a leading cause of blindness, has negative consequences for millions of people worldwide.”