Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy

Abstract

To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC). Genome-wide survival analysis using a longitudinal cohort study. We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography. We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values < 1.0× 10-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis. The association between SNPs and MNV development in patients with CSC. Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]meta, 3.63; Pmeta= 5.76× 10-9). Among previously reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR, 0.39, P= 2.55× 10-4), COL4A3 rs4276018 (HR, 0.26, P= 1.56× 10-3), and B3GALTL rs9564692 (HR, 0.56, P= 8.30× 10-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of 8 pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport. ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.