Genome-Wide Polygenic Risk Score for Predicting High Risk Glaucoma Individuals of Han Chinese Ancestry

Abstract

Glaucoma is a progressive and irreversible blindness-causing disease. However, the underlying genetic factors and molecular mechanisms remain poorly understood. Previous genome-wide association studies (GWAS) have made tremendous progress on the SNP-based disease association and characterization. However, most of them were conducted for Europeans. Since differential genetic characteristics among ethnic groups were evident in glaucoma, it is worthwhile to complete its genetic landscape from the larger cohorts of Asian individuals. Here, we present a GWAS based on the Taiwan Biobank. Among 1013 glaucoma patients and 36,562 controls, we identified a total of 138 independent glaucoma-associated SNPs at the significance level of p < 1 × 10−5. After clumping genetically linked SNPs (LD clumping), 134 independent SNPs with p < 10−4 were recruited to construct a Polygenic Risk Score (PRS). The model achieved an area under the receiver operating characteristic curve (AUC) of 0.8387 (95% CI = [0.8269–0.8506]), and those within the top PRS quantile had a 45.48-fold increased risk of glaucoma compared with those within the lowest quantile. The PRS model was validated with an independent cohort that achieved an AUC of 0.7283, thereby showing the effectiveness of our polygenic risk score in predicting individuals in the Han Chinese population with higher glaucoma risks.

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study

“…A decrease in risk attributable to PRS tertile in later phases of OHTS, is most likely due to an increasing contribution of age or cumulative environmental burden. While the increase in absolute risk appears lower than the 6 to 45-fold increases seen in other studies, it is important to note that our study includes only OHTN patients with healthy optic nerves at baseline, but increased risk of conversion compared to those with normal IOP 20,40,41 . Furthermore, OHTN patients who do not develop glaucoma may have undiscovered protective variants not captured by our PRS.…”

Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study

“…While the increase in absolute risk appeared lower than the 6-fold to 45-fold increases seen in other studies, it is important to note that our study includes only patients with OHTN with healthy optic nerves at baseline but increased risk of conversion compared with those with normal IOP. 20,43,44 Furthermore, low-risk patients may have undiscovered protective variants not captured by our PRS. Analysis of collinearity between PRS and other baseline covariates only showed a significant association with mean (SD) VCDR, with a modest increase from 0.36 (0.20) to 0.43 (0.20) from the lowest to highest PRS tertile (Table ).…”

“…The decreased risk attributable to PRS tertile in later phases of OHTS was most likely due to increasing contributions of age or cumulative environmental burden. While the increase in absolute risk appeared lower than the 6-fold to 45-fold increases seen in other studies, it is important to note that our study includes only patients with OHTN with healthy optic nerves at baseline but increased risk of conversion compared with those with normal IOP . Furthermore, low-risk patients may have undiscovered protective variants not captured by our PRS.…”