Development and Validation of Polygenic Scores for Retinal Vessel Calibers

Retinal vessel calibers are genetically heritable, quantitatively measured, and noninvasive ocular biomarkers of microvascular health. Despite their heritability identified from genome-wide association studies (GWASs), polygenic scores (PGSs) for these traits have not been developed. We aimed to calculate PGSs and associate them with retinal vessel caliber phenotypes in older adults.

Our study included 3717 individuals of European ancestry aged ≥70 years with retinal imaging and genome-wide genotype data. Retinal vessel calibers were measured from fundus photographs and summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE). PGSs for each trait were constructed using the SBayesRC method, incorporating prior GWAS summary statistics. Associations between PGSs and measured CRAE and CRVE were examined using linear regression, adjusting for demographic and clinical covariates.

Both PGSs were associated with their corresponding retinal vessel calibers. In fully adjusted models, each standard deviation increase in the CRAE and CRVE PGSs was associated with a 1.53 and 3.89 µm increase in vessel diameter, respectively (both P < 0.0001). Fully adjusted models explained 6.0% of CRAE and 7.1% of CRVE variance. A dose-response pattern was observed across increasing PGS quartiles for CRAE and CRVE. Participants in the highest PGS quartile, versus the lowest, had 4.23 µm wider arterioles for CRAE, and 9.50 µm wider venules for CRVE (both P < 0.0001).

PGSs for CRAE and CRVE are associated with measured retinal microvascular phenotypes. These findings illustrate the genetic contribution to retinal vessel calibers and provide insights into mechanisms of microvascular and macrovascular health.