By Rebecca Salowe

Scheie Vision Summer 2021


Researchers at the Scheie Eye Institute have been awarded a five-year, $6.6 million National Eye Institute (NEI) grant renewal to investigate genetic variants associated with primary open-angle glaucoma (POAG) in African Americans. This grant builds upon the original $11.2 million study, funded in 2014, which recruited and genotyped 10,255 African American individuals from Philadelphia.


“In our original grant, we focused on enrolling African Americans from the Philadelphia community, genotyping these individuals, and identifying variants associated with this disease,” explained Joan O’Brien, MD, Principal Investigator of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. “Now, we seek to understand the biological importance of these variants. Our long-term goal is to translate this information into more personalized and targeted diagnostic and therapeutic strategies for this overaffected and understudied population.”


POAG is a familial disease that affects 53 million individuals worldwide, with African Americans facing a disproportionate burden of disease. Current treatment options aim to lower the pressure in the eye but are insufficient to prevent vision loss in roughly one-third of patients.


“Our findings suggest that POAG has additional underlying disease mechanisms that are independent of elevated eye pressure,” said Dr. O’Brien. “We know that there is a genetic component to the disease, as family history has a strong influence. Genetic studies can help to elucidate other disease mechanisms, providing further therapeutic targets.”


African Americans are five times more likely to be affected by POAG than European Americans and up to 15 times more likely to experience subsequent vision loss. Despite this increased burden of disease, the majority of genetic studies of POAG have focused on populations of European and Asian descent. Many of the variants discovered in these studies do not replicate in the genetically diverse African American population.


The POAAGG study sought to address this disparity. Over its five years of funding, the study enrolled 10,255 African American individuals from the city of Philadelphia. These individuals were recruited from ophthalmology clinics at the University of Pennsylvania (UPenn) and external sites, the Penn Medicine Biobank, and community outreach efforts.


“Community outreach was an essential part of this study,” said Marquis Vaughn, Community Outreach Coordinator. “We sought to reach individuals without access to care through many different methods throughout the years. For example, we purchased a van to conduct free glaucoma screenings throughout the city. We also partnered with local community leaders and radio stations to spread word about the study and glaucoma risk.”


A genome-wide association study (GWAS) was performed on cases and controls in this population, using a SNP array with custom content to maximize coverage of variants in admixed populations. Whole-exome sequencing was also completed on subjects in collaboration with the Regeneron Genetics Center.


The POAAGG study also collected extensive phenotypic information on glaucoma cases during exams by glaucoma specialists. These measurements ranged from more traditional clinical values, such as intraocular pressure and visual field testing, to more precise and unique measurements taken from images in the Scheie Image Reading Center.


“POAG is a heterogenous disease with a broad range of trait representation,” explained Harini Gudiseva, Lab Director for the Ocular Genetics Laboratory and Project Manager for the POAAGG study. “Thus, it is also important to identify variants associated with specific phenotypes. These findings can help to identify subgroups of the disease and improve predictive models for development, progression, and intervention.”


The five-year grant renewal will further leverage the vast amount of genetic data collected in the initial period of the grant. The team is seeking to validate and investigate additional variants for African American POAG using several orthogonal approaches.


First, the team plans to perform post-GWAS analyses in collaboration with Marylyn Ritchie, PhD, Director of the Center for Translational Bioinformatics at UPenn. These analyses include constructing a disease risk model, conducting a meta-analysis, and correlating phenotypes with genetic variants. They will also analyze the extensive exome sequencing data to identify rare and familial variants resulting in POAG.


In parallel, the team plans to use structural genomic approaches to explore 3D interactions in the genome. This analysis, conducted with Struan Grant, PhD, Director for the Center for Spatial and Functional Genomics at Children’s Hospital of Philadelphia, will help to identify the true effector gene associated with a variant.  Importantly, this is the very first application of this novel methodology to POAG.


Finally, the study will evaluate the functional significance of POAG-associated variants using novel cell-based and animal model systems.


“Functional studies aid in integrating causal variants/SNPs to downstream molecular pathways and allow us to capture biological insights into evaluating POAG risk and pathogenesis,” said Venkata Ramana Murthy Chavali, PhD, Research Assistant Professor of Ophthalmology and Co-Investigator on the POAAGG study. “This integrated multi-omics approach, together with functional analysis, will accelerate our understanding of POAG and lead to the development of promising therapeutic targets.”


The long-term goals of this grant renewal are to define the genetic subtypes of POAG and to develop more targeted diagnostic and therapeutic interventions.


“We hypothesize that glaucoma, much like cancer, is not one, but many diseases with various underlying causes and genetic differences,” said Dr. O’Brien. “If proven to be true, we can then name the subtypes of disease and develop precise, targeted treatments for each form.”

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