Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population.

Background: Keratoconus (KC) is a prevalent corneal condition with a modest genetic basis. Recent studies have reported significant genetic associations in multi-ethnic cohorts. However, the situation in the Chinese population remains unknown. This study was conducted to identify novel genetic variants linked to KC and to evaluate the potential applicability of a polygenic risk model in the Han Chinese population.

Methods: A total of 830 individuals diagnosed with KC and 779 controls from a Chinese cohort were enrolled and genotyped by whole-genome sequencing (WGS). Common and rare variants were respectively subjected to single variant association analysis and gene-based burden analysis. Polygenic risk score (PRS) models were developed using top single-nucleotide polymorphisms (SNPs) identified from a multi-ethnic meta-analysis and then evaluated in the Chinese cohort.

Results: The characterization of germline variants entailed correction for population stratification and validation of the East Asian ancestry of the included samples via principal component analysis. For rare protein-truncating variants (PTVs) with minor allele frequency (MAF) < 5%, ZC3H11B emerged as the top prioritized gene, albeit failing to reach the significance threshold. We detected three common variants reaching genome-wide significance (P ≤ 5 × 10), all of which are novel to KC. Our study validated three well known predisposition loci, COL5A1, EIF3A and FNDC3B. Additionally, a significant correlation of allelic effects was observed for suggestive SNPs between the largest multi-ethnic meta-genome-wide association study (GWAS) and our study. The PRS model, generated using top SNPs from the meta-GWAS, stratified individuals in the upper quartile, revealing up to a 2.16-fold increased risk for KC.

Conclusions: Our comprehensive WGS-based GWAS in a large Chinese cohort enhances the efficiency of array-based genetic studies, revealing novel genetic associations for KC and highlighting the potential for refining clinical decision-making and early prevention strategies.