Genome-wide Polygenic Risk Score for Primary Open Angle Glaucoma is Associated with More Severe Disease in a Multi-Ethnic Biobank

Abstract

Purpose : Primary open angle glaucoma (POAG) polygenic risk score (PRS) has been associated with increased risk of glaucoma, developing severe disease, maximum recorded IOP, younger age at diagnosis, and glaucoma progression. However, the utility of PRS in clinical practice is not well established. Here we aimed to evaluate the association between PRS and severity of POAG using data from a multi-ethnic clinical biobank.

Methods : A Lassosum penalized regression framework from 10238000 directly genotyped and imputed variants for UK Biobank samples (n=449186: 14171 cases, 394292 controls) was used to compute a genome-wide PRS. The calculated weights were used to compute PRS in 7689 participants with ocular data available in the Mass General Brigham Biobank. PRS were normalized within each genotype-inferred ancestral group. Participants were stratified into POAG cases and controls based on the presence of ICD codes 365.1, 365.8, 365.9, H40.1, H40.8, and H40.9. Data including intraocular pressure (IOP), cup-to-disc ratio (CDR), spherical equivalent (SE), optical coherence tomography derived macular ganglion cell complex (GCC) and optic nerve retinal nerve fiber layer (RNFL) global thicknesses were extracted. The worse measure from the worse eye was selected for each patient. Multivariable linear regression models were used to examine the association between ocular factors and PRS.

Results : Of the 7689 participants, 1077 (14%) were cases and 6612 (86%) were controls. The mean (SD) age was 67.5 (14.8) years, and 53% were female. The ancestral breakdown was 86.4% European, 6.1% Hispanic, 5.6% African, and 1.8% East/South Asian. The prevalence of POAG increased with each decile of polygenic risk and nearly tripled from 9.1% in the first decile to 24.2% in the 10^th decile (Fig. 1). After adjusting for age and sex, each SD increase in PRS was associated with 0.40 (CI:0.29,0.51; p<0.001) mmHg increase in IOP, 0.04 (CI:0.03,0.04; p<0.001) increase in CDR and -1.61 (CI: -2.84,-0.37; p=0.011) µm decrease in global RNFL thickness (Fig. 2). There was no significant association between PRS and SE or global GCC thickness.

Conclusions : Our findings suggest that underlying POAG polygenic risk increases disease prevalence and severity, supporting the use of a POAG PRS to identify individuals at high risk of POAG and potentially risk stratify patients in our clinics.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Figure 1

 

Figure 2