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Overlap Detected in Genetic Loci for Central Serous Chorioretinopathy and Age-related Macular Degeneration

Key findings

  • This three-cohort genetic association study replicated two previously reported genetic loci for central serous chorioretinopathy (CSC) and identified three novel loci near the genes NOTCH4, PREX1, and CD34/CD46
  • Three of the five loci were noted to contain complement genes
  • Expression of six genes—CFH, CD34, CD46, NOTCH4, PREX1 and LAMA5—was higher in vascular samples compared to all other ocular tissues and higher in cultured choroidal vascular endothelial cells compared to all other genes
  • A genome-wide polygenic risk score for age-related macular degeneration (AMD) was associated with decreased risk of CSC (OR, 0.76 per +1 SD in score; P = 7.4 × 10-10)
  • These findings support a role for choroidal vascular dysfunction and complement dysregulation in CSC pathogenesis and demonstrate an inverse genetic overlap between CSC and AMD

Central serous chorioretinopathy (CSC) has been observed to cluster in families and is thought to be a genetically complex disorder. A 2018 genome-wide association study (GWAS) of 521 European patients with chronic CSC, published in JAMA Ophthalmology, identified a susceptibility locus near CFH.

A later whole-genome sequencing study of Japanese patients with CSC, reported in Communications Biology, identified susceptibility loci near GATA5 and TNFRSF10A.

Interestingly, CFH and TNFRSF10A have also been found to be associated with age-related macular degeneration (AMD). Now, a study led by Elizabeth J. Rossin, MD, PhD, a vitreoretinal surgeon and scientist in the Department of Ophthalmology at Mass Eye and Ear, and Joel Rämö, MD, PhD, a scientist at the Broad Institute, have identified three novel genetic risk loci for CSC, including one associated with reduced risk of AMD. Their data appear in a new paper in JAMA Ophthalmology.

Three-Cohort Meta-Analysis

The researchers performed a meta-analysis of the published European GWAS and their own GWASs of two national biobanks, FinnGen and Estonian Biobank. In both biobanks, individuals with CSC were identified using diagnosis codes. Exclusion criteria included AMD and choroidal disorders. Altogether, there were 1,176 cases and 526,787 controls.

Five loci reached genome-wide significance: the two previously reported loci near CFH and GATA5 and three novel loci near the NOTCH4, PREX1, and CD34/CD46 genes. The susceptibility locus near TNFRSF10A was just below their significance threshold, but its effect size was comparable to prior reports, and the authors suspect it will replicate in the future. Effect estimates were concordant across the three cohorts without significant heterogeneity.

Gene Set Enrichment and Gene Prioritization

Genes regulating the complement activation pathway were significantly associated with CSC. No other molecular pathway reached significance.

The prioritized genes (those most likely to be associated with CSC) were CFH, CD34, CD46, NOTCH4, PREX1, LAMA5, and GATA5.

Gene Expression in Choroidal Endothelium

Expression of six prioritized genes—CFH, CD34, CD46, NOTCH4, PREX1, and LAMA5—was higher in vascular cells than in retina, retinal pigment epithelium, or rods and cones, and this was replicated in an expression assay involving cultured choroidal endothelial cells. This finding corroborates previous research suggesting a role for choroidal vascular dysfunction in CSC pathogenesis.

Individual-level Risk of CSC vs. AMD

Using data from FinnGen, the researchers constructed a genome-wide polygenic risk score for AMD, incorporating data on 1,077,835 variants. The score was associated with decreased risk of CSC (OR, 0.76 per +1 SD in score; P = 7.4 × 10−10).

The score's association with CSC was markedly reduced when CFH was removed from the analysis. It was even further attenuated when six complement-annotated loci were removed.


These observations highlight a likely role between CSC and genes involved in choroidal vascular function and complement regulation. The genetic overlap between CSC and AMD is largely due to the loci containing complement genes, and further study will be needed to understand the implications.

less risk of central serous chorioretinopathy for every standard deviation increase in a genome-wide polygenic risk score for age-related macular degeneration

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