Genetic Architecture of Choroidal Vascularity Revealed by Population-scale Retinal Imaging

Background and Aim: The choroid is a highly vascular tissue essential for retinal homeostasis, and its remodeling particularly venous congestion is a hallmark of pachychoroid diseases such as central serous chorioretinopathy. The choroidal vascularity index (CVI), a quantitative ratio of vascular to total choroidal area derived from optical coherence tomography (OCT), captures inter-individual variation in choroidal vascular structure. However, the genetic determinants of CVI and their biological implications remain unknown. Here, we aimed to define the genetic architecture of CVI using population-scale OCT imaging. Methods: We developed a scalable automated pipeline integrating image processing and rule-based vessel segmentation to extract three-dimensional CVI phenotypes from macular OCT volumes. We applied this framework to OCT data from 62,751 UK Biobank participants after quality control. Genome-wide association studies were performed for CVI mean and spatial variability, adjusting for demographic, ocular, and genetic covariates. Associated loci were interpreted using gene-based analyses. Results: We identified 12 independent loci across nine chromosomes associated with CVI traits. CVI mean was enriched for loci linked to systemic vascular and hematologic pathways, including ABO and VWF, whereas CVI variability showed stronger associations with inflammatory and complement-related genes, notably CFH, previously implicated central serous chorioretinopathy, a pachychoroid disease. Additional loci highlighted roles for mitochondrial function, metabolism, pigmentation, and oxidative stress. Conclusion: Our results establish CVI as a heritable imaging endophenotype and reveal distinct genetic contributions to average choroidal vascularity and its spatial heterogeneity. These findings link choroidal vascular remodeling to systemic vascular, inflammatory, and metabolic pathways, providing a framework for integrating ocular imaging with genetic studies of microvascular disease.