Glaucoma Genetic Risk Scores in the Million Veteran Program

Abstract

Purpose: Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).

Design: Cross-sectional study.

Participants: MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.

Methods: We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.

Main outcome measures: Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.

Results: GRS were significantly associated with POAG (P < 5 × 10^-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.

Conclusions: Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Keywords: Ancestral diversity; Genetic risk score; Invasive glaucoma surgery; Million Veteran Program; Primary open-angle glaucoma.

Figure 1.. Schematic overview of study design.

GRS were calculated for POAG cases and controls in the MVP with imputed genetic data and harmonized ancestry and race/ethnicity data. We performed logistic regression-based association analyses of the weighted and unweighted 127-variant GRS with POAG case-control status as well as IGS status. Receiver operator characteristic (ROC) curves for both unadjusted and adjusted models were constructed to evaluate GRS performance. Abbreviations: POAG = primary open-angle glaucoma, AFR = non-Hispanic African ancestry, EUR = non-Hispanic European ancestry, GRS = genetic risk score, IGS = invasive glaucoma surgeries, GDI = glaucoma drainage implants, PCs = principal components.

Figure 2.. Comparison of performance of 127-variant POAG GRS in AFR and EUR Veterans.

Log odds ratios (betas) for unadjusted logistic regression-based association analyses are shown across increasing deciles of (A) unweighted, (B) cross-ancestry meta-weighted, and (C) ancestry-specific GRS for AFR and EUR Veterans. In panels A-C, deciles 5–6 (40–60%) are used as the reference and denoted by the dashed line. A full description of log odds ratios for panels A-C are shown in Table S3 (available at www.aaojournal.org). ROC curves are shown for (D) unweighted, (E) cross-ancestry meta-weighted, and (F) ancestry-specific GRS performance in AFR and EUR Veterans. AFR and EUR AUCs are listed in the inset with their 95% confidence intervals in parentheses. Abbreviations: AFR = non-Hispanic African ancestry, EUR = non-Hispanic European ancestry, GRS = genetic risk scores, AUC = area under the curve, ROC = receiver operator characteristic.

Figure 3.. Comparison of POAG case classifications based on 127-variant POAG GRS in AFR and EUR Veterans.

Case proportions are shown for each decile of the (A) unweighted, (B) meta-weighted, and (C) ancestry-specific weighted GRS by ancestry group. Case proportion by decile indicates the number of POAG cases in each decile divided by the total number of POAG cases in the MVP. Abbreviations: AFR = non-Hispanic African ancestry, EUR = non-Hispanic European ancestry.

Figure 4.. Comparison of GRS deciles for any IGS in POAG patients in the MVP.

Log odds ratios (betas) for unadjusted logistic regression-based association analyses are shown for deciles of (A) unweighted, (B) cross-ancestry meta-weighted, and (C) ancestry-specific GRS for AFR and EUR Veterans. In all panels, deciles 1–9 (bottom 90%) were compared to decile 10 (top 10%). A full description of log odds ratios (betas) for panels A-C are shown in Table S8 (available at www.aaojournal.org). Abbreviations: AFR = non-Hispanic African ancestry, EUR = non-Hispanic European ancestry, GRS = genetic risk score, IGS = invasive glaucoma surgery.