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

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.

Hospital-based cross-sectional genetic association study.

A total of 576 participants from Tianjin Eye Hospital were included, comprising 443 individuals with myopia, 105 with HM, and 28 with EHM.

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.

Associations of PRS with myopia severity and ocular structural phenotypes, particularly AL and SE; severity-stratified genome-wide association signals in HM and EHM.

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.

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.

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