GWAS meta-analysis identifies 10 CSC loci and links genetic risk to OCT abnormalities

Photo by digitale.de / Unsplash

medRxiv Published May 23, 2026 Medically reviewed May 23, 2026 Study authors: Chen, L.; Kim, S. H.; Truong, B.; Rämö, J. T.; Gorman, B. R.; van Dijk, E. H. C.; Brinks, J.; Niko… DOI ↗ By Dr. Lars van Dijk, PhD · Surgical, Procedural & Diagnostic

Key Takeaway

Consider that a high CSC genetic risk score is associated with more frequent OCT abnormalities in observational data.

This is a GWAS meta-analysis of central serous chorioretinopathy (CSC) using data from European-ancestry cohorts. The study included 2,584 cases and 1,044,455 controls from FinnGen, All of Us, Mass General Brigham Biobank, Million Veteran Program, and a Dutch chronic CSC cohort.

The authors identified 10 loci that reached genome-wide significance (P < 5e-8). Three of these are novel loci near TGFB1, LINC00551, and LOC105375630, while 7 are replicated loci near CFH, CD46, NOTCH4, PREX1, PTPRB, GATA5, and TNFRSF10A. A CSC genetic risk score was constructed, and in the top 1% of genetic risk, OCT abnormalities were more frequent than in the bottom 1% (odds ratio, 4.05; 95% CI, 1.65-10.87; P = .002). Specifically, 18 of 109 individuals (16.5%) in the top risk group had OCT abnormalities versus 8 of 134 (6.0%) in the bottom risk group.

The authors note that colocalization and Mendelian randomization implicated circulating TNFRSF10A, TGFB1, and CASP10 levels. The analysis also included single-cell disease-relevance scoring and assessment of the CSC genetic risk score in UK Biobank OCT images.

The authors acknowledge limitations, though none are detailed in the provided information. The practice relevance is that these findings support CSC as a sclerovascular disorder and nominate complement regulation, endothelial signaling, and extracellular matrix pathways for future study. The evidence is observational and does not establish causality.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

Objective: To define CSC genetic architecture and identify implicated ocular tissues, cell types, genes, and circulating proteins. Data Sources: Genome-wide data were assembled from FinnGen, All of Us, Mass General Brigham Biobank, Million Veteran Program, and a Dutch chronic CSC cohort. Serum protein quantitative trait loci, human single-cell ocular atlases, and UK Biobank macular optical coherence tomography (OCT) imaging were used for downstream analyses. Study Selection: Five European-ancestry cohorts with genome-wide data and cohort-specific CSC case-control definitions were included, comprising 2,584 cases and 1,044,455 controls. Variants present in at least 2 cohorts were meta-analyzed. Data Extraction and Synthesis: Cohort-level GWASs were adjusted for age, age squared, sex, genotyping array or batch, and 10 genetic principal components, then combined using fixed-effects inverse-variance meta-analysis. Post-GWAS analyses included gene prioritization, colocalization, Mendelian randomization, single-cell disease-relevance scoring, and testing of a CSC genetic risk score in UK Biobank OCT images. Main Outcome(s) and Measure(s): Genome-wide significant CSC loci, effector genes and proteins, tissue and cell-type enrichment, and CSC-relevant OCT abnormalities. Results: Across 11,068,938 variants, 10 loci reached genome-wide significance (P < 5e-8), including 3 novel loci near TGFB1, LINC00551, and LOC105375630 and 7 replicated loci near CFH, CD46, NOTCH4, PREX1, PTPRB, GATA5, and TNFRSF10A. Integrative analyses prioritized 10 candidate effector genes. Colocalization and Mendelian randomization implicated circulating TNFRSF10A, TGFB1, and CASP10 levels. Single-cell analyses localized genetic risk to sclera (P = 2.0e-4) and vascular endothelial cells (P = 4.0e-4), with fibroblast enrichment. In UK Biobank, OCT abnormalities were more frequent in the top vs bottom 1% of CSC genetic risk (18 of 109 [16.5%] vs 8 of 134 [6.0%]; odds ratio, 4.05; 95% CI, 1.65-10.87; P = .002). Conclusions and Relevance: In this GWAS meta-analysis, CSC susceptibility localized predominantly to scleral and vascular biology rather than primary retinal pigment epithelial dysfunction. These findings support CSC as a sclerovascular disorder and nominate complement regulation, endothelial signaling, and extracellular matrix pathways for future study.