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

Area of Science:

• Ophthalmology
• Genetics
• Medical Research

Background:

• High myopia (HM) and extreme high myopia (EHM) have complex genetic underpinnings.
• Understanding the genetic architecture of myopia severity is crucial for targeted interventions.

Purpose of the Study:

• To integrate polygenic risk scoring (PRS) with detailed ocular phenotyping.
• To investigate the genetic architecture related to severity in high myopia (HM) and extreme high myopia (EHM) within a Chinese cohort.

Main Methods:

• Whole-genome sequencing was performed on 576 participants.
• Polygenic risk scores (PRS) were constructed using external GWAS data for refractive error.
• Ocular traits including axial length (AL) and spherical equivalent (SE) were analyzed.

Main Results:

• Higher PRS was significantly associated with longer AL and more negative SE.
• Each 1-SD increase in PRS correlated with a 0.174-mm increase in AL and a -0.498-diopter shift in SE.
• Severity-stratified GWAS revealed partially overlapping genetic signals for HM and EHM.

Conclusions:

• Polygenic burden is associated with increasing myopia severity, mainly via axial elongation.
• These findings enhance understanding of common-variant genetic risk in severe myopia.
• Further research is needed, especially for EHM due to limited sample size.