Genotype-Phenotype Analysis Of Keratoconus In The Han Chinese Population By Whole-Genome Sequencing
Published 2025 - 43rd Congress of the ESCRS
Reference: FP03.01 | Type: Free paper | DOI: 10.82333/p6eh-5h18
Authors: Maximilian Friedrich* 1 , Hyeck-Soo Son 1 , Timur M. Yildirim 1 , Gerd U. Auffarth 1 , Victor A. Augustin 1
1Department of Ophthalmology,University Hospital Heidelberg,Heidelberg,Germany
Purpose
Keratoconus (KC) is a corneal disorder with modest heritability and strong genetic associations across diverse populations. However, genetic studies in the Han Chinese population remain limited, and genotype-phenotype correlations are poorly understood. This study aimed to characterize these correlations and identify novel pathogenic genes in KC.
Setting
A prospective cohort study
Methods
Whole genome sequencing (WGS) was performed on 335 KC patients and 658 matched controls from the Han Chinese population. Pathogenic or likely pathogenic (P/LP) variants were analyzed for associations with KC phenotypes, focusing on enriched Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Rare variant association analysis was conducted to identify novel candidate genes.
Results
Among 89,255 variants, 3.6% were P/LP. Rare variants in extracellular matrix organization and fatty acid metabolism pathways correlated with severe KC phenotypes. KEGG analysis linked six pathways (e.g., ABC transporters, protein digestion, and retinol metabolism) to more severe KC. Variants in eight well-characterized KC gene sets also exacerbated phenotypes, affecting corneal thickness, curvature, and biomechanical parameters. Notably, some pathways increased glaucoma risk, such as fatty acid metabolism (elevated intraocular pressure) and protein digestion (reduced anterior chamber volume). Gene-based analysis identified three novel candidate genes (TRIM17, PDE4D, THADA) with corneal expression.
Conclusions
P/LP variants in specific pathways and gene sets influence KC severity and phenotype variability, with some pathways potentially increasing glaucoma risk. TRIM17, PDE4D, and THADA are implicated as novel KC-associated genes, offering insights into KC pathogenesis.