PAGE-G: Precision Approach combining Genes and Environment in Glaucoma

PROJECT SUMMARY/ABSTRACT
Glaucoma is the world’s leading cause of irreversible blindness and is projected to affect >110 million people
by 2040. Risk stratification is important in order to identify individuals at high risk of glaucoma, since early
detection and treatment can help decrease the risk of irreversible vision loss. Because glaucoma has a high
level of heritability, polygenic risk scores (PRS) have been developed to examine risk stratification based on
genetic variants. However, because genome-wide association studies have most commonly been performed in
European descent populations, PRS may not generalize well to non-European descent populations. This is a
major issue for glaucoma given that non-European descent populations carry a disproportionate burden of
glaucoma, including earlier age of onset, faster disease progression, and higher risk of vision loss.
The All of Us Research Program offers an opportunity to further improve PRS models for glaucoma and
enhance a precision medicine approach for this complex condition. First, the recent release of whole genome
sequencing data on the All of Us Researcher Workbench provides additional genomic data from a diverse
cohort of participants to add to the growing literature of genomic studies in glaucoma. We plan to develop a
wide array of PRS models that will be trained and tested on data from All of Us (Aim 1). Further, we will
leverage an innovative tool that annotates variants according to their regulatory activity in disease-specific cell
types (in this case, eye tissues) to improve the predictive accuracy of trans-ancestry PRS models (i.e., make
models trained on one population more widely generalizable to other populations) (Aim 2). Finally, because All
of Us includes detailed data regarding environmental factors such as clinical data, healthcare access and
utilization, and social determinants of health, it represents a unique opportunity to better understand gene-
environment interactions in glaucoma and further refine risk stratification by simultaneously analyzing a
multitude of data types (Aim 3).
This study aims to improve PRS for glaucoma by enhancing performance via the strategies outlined above.
Additionally, these aims may potentially uncover new risk variants and generate new insights regarding their
functional importance. These will represent important advancements in precision medicine in glaucoma,
particularly for diverse populations who have been traditionally underrepresented in biomedical research yet
are most severely affected by this blinding eye disease.

Grant Number: 1R03EY035824-01
NIH Institute/Center: NIH
Principal Investigator: Sally Baxter