Genome-wide association study meta-analysis in CSCR points to genes important in vascular tissue

Abstract

Purpose : Central serous chorioretinopathy (CSCR) is a common fluid maculopathy associated with vision loss. CSCR onsets between age 40-50 and thus has a longer life burden than other later-onset degenerative eye diseases. The etiology is not understood which has contributed to a relative lack of therapeutic advances. While CSCR has been noted to track in families, sample sizes have been inadequate to calculate heritability; still, knowledge of genetic underpinnings can provide a window into disease biology. The purpose of this study is to conduct the largest GWAS meta-analysis to date by combining 2 biobank-based cohorts and 1 clinic-based cohort and expand the pool of genome-wide significant (GWS) loci associated to CSCR.

Methods : Patients from biobanks were ascertained based on an ICD-10 code of H35.7 (FinnGen) or H35.71 (Million Veterans Program; MVP), and controls were those without. Age-related macular degeneration (AMD) was excluded from all cases and controls. We identified a total of 2,319 patients and 762,167 controls, including 1,092 patients and 485,392 controls from the FinnGen study, 706 cases and 273,198 controls from MVP and 521 cases and 3,577 controls from a previously published European cohort. We conducted new GWAS in the FinnGen and MVP cohorts and meta-analyzed all cohorts.

Results : We identify 10 independent loci associated to CSCR that reach GWS (P < 5 x 10^-8). A SNP-wise heritability (h²) estimate using LD-score regression was 0.0981 (SE 0.0226). In cultured choroidal endothelial cells, genes in GWS loci were more highly expressed than expected by chance (P = 8.4 x 10^-4). Single-cell expression in ocular tissues highlighted retinal and choroidal capillaries, arteries and veins as most robustly expressing associated genes. Pathway analysis further pointed to a central role for genes involved in complement binding (P = 8.5 x10^-10) and cell adhesion (3.2 x 10^-10). Of note, 5 CSCR loci are among the known associated loci for AMD, but 3 are in the opposite risk direction, suggesting overlapping but discordant genetic risk for CSCR and AMD.

Conclusions : Doubling prior sample sizes, our meta-analysis reports 10 loci (5 of which are novel) associated with CSCR. Genes in these loci point to alterations in the vasculature as driving pathology, rather than destruction of the retinal pigment epithelium (RPE), and this distinction is critical to our understanding of CSCR etiology.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.