Choroidal Vascular Dysfunction-Causing Genes Lead to Central Serous Chorioretinopathy

Genetic loci can be associated with the development of central serous chorioretinopathy and genetic overlap exists between central serous chorioretinopathy and age-related macular degeneration.

Choroidal vascular dysfunction and related genetic loci can foretell risk for central serous chorioretinopathy (CSC), according to a study published in JAMA Ophthalmology. Researchers reproduced prior findings of 2 genetic risk loci for CSC and discovered 3 novel loci that suggest the disorder’s origin is related to choroidal vascular dysfunction, as well as that loci common to CSC and age-related macular degeneration (AMD) contain complement genes. This is the first genome-wide association study meta-analysis for CSC.

Researchers analyzed records from 3 large cohorts: 552 patients with CSC, 343,461 healthy participants from the FinnGen Data Freeze 9, as well as 103 patients and 178,573 control participants in Estonian Biobank (EstBB). CSC was identified by International Classification of Diseases (ICD-9 and ICD-10) codes. A meta-analysis was then performed by also incorporating data of a published European set of 521 records of patients with chronic CSC and 3577 healthy individuals.

The already recognized loci for CSC risk — near CFH and GATA5 were again demonstrated in this analysis, and 3 novel loci; CD34/CD46, NOTCH4, and PREX1 attained significance across the combined genome, as well. Of these novel loci, NOTCH4 and CD34/CD46 have been previously linked with immune function choroidal vascular dysfunction. Notably, the study found a partial genetic overlap of CSC and AMD — CFH and NOTCH4 were linked to AMD, although with an inverse trend from CSC — overlap likely occurred via loci having complement genes.

In multi-gene loci, genes were prioritized with polygenic priority scores to consider factors such as gene expression. “Prioritized genes in the loci (CFH, CD34, CD46, NOTCH4, PREX1, and LAMA5) are particularly expressed in choroidal vascular endothelial cells compared with retina and [retinal pigment epithelium], which corroborates a role for choroidal vascular dysfunction in CSC pathogenesis,” according to the study. Expression in cultured endothelial cells vs nearby genes was significant (P =.004).

Previous studies show the NOTCH4 protein regulates endothelial vascular development and is expressed in cells that researchers suspect are involved in choroidal neovascularization. Other complement genes, such as CD34, have also been reported to be suspected in AMD pathogenesis.

Limitations of the investigation include identification of CSC via ICD coding, and European-only datasets, possibly affecting generalizability. Additionally, cohorts were of different sizes.

Disclosure: Some study authors declared affiliations with the biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Ramo JT, Abner E, van Dijk EHC, et al. Overlap of genetic loci for central serous chorioretinopathy with age-related macular degeneration. JAMA Ophthalmol. Published online April 20, 2023. doi:10.1001/jamaophthalmol.2023.0706