Optimizing genetic risk models for primary open-angle glaucoma through expanded population genomic analysis

East Carolina University, Greenville NC

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Abstract

Glaucoma is a leading cause of irreversible vision loss worldwide and is a complex disease influenced by genetics. POAG, the most common subtype of glaucoma, often presents earlier and progresses faster in individuals from continental American and African genetic ancestry and with higher proportions. Large-scale genetic studies to date, which inform clinical genetic risk models, prioritize continental European genetic ancestry, thereby limiting their potential to inform early detection and clinical management. This narrowed focus in POAG genetic studies reduces both the accuracy and applicability of existing POAG polygenic risk scores (PRS) and limits development of new PRS that accurately incorporate the range of genetic variation present in individuals with American, African, and European continental genetic ancestry - i.e. the majority of individuals at risk for POAG. This study will enhance risk prediction for POAG by bringing together and harmonizing clinical and genetic data from the largest worldwide available datasets of POAG case-control information from populations with American, African, and European genetic ancestry with three aims. In Aim 1, we will conduct meta-analyses of existing genome-wide association studies (GWAS) to identify and characterize novel POAG loci. In Aim 2, we will leverage admixture mapping to identify genomic regions where continental genetic ancestry is associated with POAG risk. Significant loci from Aims 1 and 2 will be fine-mapped and evaluated for selection signatures to improve resolution of causal variants. In Aim 3, we will develop and optimize ancestry-informed PRS for POAG classification and clinically-relevant POAG endophenotypes. This project will enhance understanding of POAG genetics across genetic backgrounds and develop risk prediction tools that more accurately reflect the range of genetic variation present in African, American, and European ancestry groups. These efforts will advance the potential for personalized risk assessment, early detection, and clinical management of POAG.