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

Objective: To integrate polygenic risk scoring with detailed ocular phenotyping to investigate severity-related genetic architecture in high myopia (HM) and extreme HM (EHM) in a clinically deeply phenotyped Chinese cohort. Design: Hospital-based cross-sectional genetic association study. Participants: A total of 576 participants from Tianjin Eye Hospital were included, comprising 443 individuals with myopia, 105 with HM, and 28 with EHM. Methods: 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. Detailed ocular phenotyping included axial length (AL), spherical equivalent (SE), sphere, cylinder, and inter-eye asymmetry metrics. Associations between PRS and ocular traits were assessed using correlation analyses and multivariable linear regression models adjusted for age and sex. Severity-stratified genome-wide association analyses were further performed for HM and EHM. Main Outcome Measures: Associations of PRS with myopia severity and ocular structural phenotypes, particularly AL and SE; severity-stratified genome-wide association signals in HM and EHM. Results: Polygenic risk score increased progressively across severity groups. Higher PRS was significantly associated with longer AL and more negative SE. In multivariable models, each 1-standard deviation increase in PRS was independently associated with a 0.174-mm increase in AL and a -0.498-diopter shift in SE, but was not significantly associated with cylinder. Severity-stratified genome-wide analyses suggested partially overlapping but nonidentical signal landscapes between HM and EHM. However, findings from the EHM subgroup should be interpreted cautiously because of 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. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.