Integrating Polygenic Risk and Ocular Phenotyping Reveals an Axial-Length-Dominant Mechanism in High and Extreme High Myopia

Abstract Background High myopia (HM) and extreme high myopia (EHM) are major causes of irreversible visual impairment. Previous genome-wide association studies have established a substantial polygenic contribution to myopia, but the relationship between polygenic burden, ocular structural phenotypes, and severity-defined extreme myopia in clinically deeply phenotyped Chinese cohorts remains incompletely characterized. We therefore integrated polygenic risk scoring with detailed ocular phenotyping to investigate severity-related genetic architecture in HM and EHM. Methods We analyzed 576 participants from Tianjin Eye Hospital (myopia, n=443; HM, n=105; EHM, n=28) whose genomic DNA obtained from oral swab samples underwent whole-genome sequencing at an average coverage of approximately 20×. Polygenic risk scores (PRS) were constructed using external genome-wide association study summary statistics for refractive error. Ocular phenotyping included axial length, spherical equivalent, sphere, cylinder, and inter-eye asymmetry metrics. Associations between PRS and ocular traits were assessed using correlation analysis and multivariable linear regression adjusted for age and sex. Severity-stratified genome-wide association analyses were further performed for HM and EHM. Results PRS increased progressively across severity groups. Higher PRS was significantly associated with longer axial length and more negative spherical equivalent. In multivariable models, each 1-SD increase in PRS was independently associated with a 0.174-mm increase in axial length and a –0.498-D shift in spherical equivalent, but not with cylinder. Stratified genome-wide analyses suggested partially overlapping yet non-identical signal landscapes between HM and EHM; however, findings from the EHM subgroup should be interpreted cautiously given the limited sample size. Conclusions Polygenic burden is associated with increasing myopia severity and appears to influence refractive status primarily through axial elongation. These findings provide additional insight into the relationship between common-variant genetic risk and structural ocular phenotypes in severe myopia.