Polygenic Risk Score Improves Cataract Prediction in East Asian Population

Abstract

Cataracts, characterized by crystalline lens opacities in human eyes, is the leading cause of blindness globally. Due to its multifactorial complexity, the molecular mechanisms remain poorly understood. Larger cohorts of genome-wide association studies (GWAS) are needed to investigate cataracts’ genetic basis. In this study, a GWAS was performed on the largest Han population to date, analyzing a total of 7079 patients and 13,256 controls from the Taiwan Biobank (TWB) 2.0 cohort. Two cataract-associated SNPs with an adjustment of p < 1 × 10−7 in the older groups and nine SNPs with an adjustment of p < 1 × 10−6 in the younger group were identified. Except for the reported AGMO in animal models, most variations, including rs74774546 in GJA1 and rs237885 in OXTR, were not identified before this study. Furthermore, a polygenic risk score (PRS) was created for the young and old populations to identify high-risk cataract individuals, with areas under the receiver operating curve (AUROCs) of 0.829 and 0.785, respectively, after covariate adjustments. Younger individuals had 17.45 times the risk while older people had 10.97 times the risk when comparing individuals in the highest and lowest PRS quantiles. Validation analysis on an independent TWB1.0 cohort revealed AUROCs of 0.744 and 0.659.

Keywords: Asian population; biobank; cataract; genome-wide association studies; polygenic risk score; retrospective study.

Figure 1

Manhattan plot showing the SNPs associated with cataracts identified from TWB2.0. Older cataract cases (≥60 years old, n = 5120) are shown in the top panel, while younger cataract cases (<60 years old, n = 1959) are shown in the bottom panel.

Figure 2

Comparison of cataract risks in TWB2.0 classified by PRS quantile. (A) Distribution of the polygenic risk score (PRS_younger) in younger cataract cases (<60) and controls. (B) Distribution of younger cases and controls according to PRS_younger quantiles. (C) Odds ratio for developing cataract in younger population according to PRS_younger quantiles. (D–F) are the cataract risks classified by PRS_older in older populations (≥60 years old).

Figure 3

Receiver operating characteristic (ROC) curves for the polygenic risk score (PRS) model. (A) PRS_younger refers to younger cataract cases (<60), and (B) PRS_older refers to the older cataract cases (≥60).