Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration

Abstract

ImportanceCentral serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases.ObjectiveTo identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD.Design, Setting, and ParticipantsUsing International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022.Main Outcomes and MeasuresGenome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study.ResultsA total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5) and 3 novel loci were identified (near CD34/46, NOTCH4, and PREX1). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million], 7.3 [0.6] vs 4.7 [3.7]; P = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P < 7.1 × 10−20). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P = 7.4 × 10−10). This association may have been mediated by loci containing complement genes.Conclusions and RelevanceIn this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.

What Can We Learn From the Surprising Insight Into the Genetic Background of Age-Related Macular Degeneration and Central Serous Chorioretinopathy?

“…PGS or PRS is not currently used in a clinical setting for diagnosis due to multiple limitations, and its variability in different ethnicities means that it can be invalid for diverse populations. This is also shown in the study by Rämö et al, in that a significant variant in 1 biobank was not significant in the other and vice versa, until a meta-analysis was performed. This may be due to sample size but may also be due to genetic ancestry, raising significant doubt regarding their involvement in the pathogenesis of the diseases.…”

“…Polygenic priority score (PPS) and nearest-gene methods were used to assess prioritized genes in the associated loci in publicly available cultured choroidal endothelial cells and ocular single-cell RNA sequencing data sets. Two of the 5 reported loci ( CFH and some of the genes in the NOTCH4 locus) were oppositely associated with AMD in this analysis …”

“…Although mendelian inheritance is unlikely in this case, a multifactorial etiology involving acquired environmental risk factors together with genetic susceptibility factors may consist of the pathological basis of CSC. The meta-analysis by Rämö and his colleagues replicated 2 previously reported risk loci (near CFH and GATA5 ) and identified an additional 3 novel risk alleles (near CD34/46 , NOTCH4 , and PREX1 ) in a total of 1176 patients with CSC compared with 526 787 controls, using a genome-wide association study (GWAS). Polygenic priority score (PPS) and nearest-gene methods were used to assess prioritized genes in the associated loci in publicly available cultured choroidal endothelial cells and ocular single-cell RNA sequencing data sets.…”

“…Both CFH and TNFRSF10A loci were previously associated with AMD . However, the TNFRSF10A locus was not identified in the study by Rämö et al In a cohort from Japan, a CFH allele that is associated with high risk for AMD was also associated with increased choroidal thickness among patients with CSC. However, this locus was inversely associated in the CSC cohort with both choroidal thickness and with development of CSC.…”

“…The findings of Rämö et al can be potentially clinically important in several aspects including a better understanding of the pathogenesis, improving diagnostic and prognostic determinations, and even future therapeutic implications. First, the identification of genetic markers of multifactorial diseases such as CSC can improve risk stratification toward precision medicine, especially in borderline undiagnosed cases.…”