TY - JOUR
T1 - Overlap of Genetic Loci for Central Serous Chorioretinopathy with Age-Related Macular Degeneration
AU - Rämö, Joel T.
AU - Abner, Erik
AU - van Dijk, Elon H. C.
AU - Wang, Xin
AU - Brinks, Joost
AU - Nikopensius, Tiit
AU - Nõukas, Margit
AU - Marjonen, Heidi
AU - Silander, Kaisa
AU - Jukarainen, Sakari
AU - Kiiskinen, Tuomo
AU - Choi, Seung Hoan
AU - Kajanne, Risto
AU - Mehtonen, Juha
AU - Palta, Priit
AU - Lubitz, Steven A.
AU - Kaarniranta, Kai
AU - Sobrin, Lucia
AU - Kurki, Mitja
AU - Yzer, Suzanne
AU - Ellinor, Patrick T.
AU - Esko, T. nu
AU - Daly, Mark J.
AU - den Hollander, Anneke I.
AU - Palotie, Aarno
AU - Turunen, Joni A.
AU - Boon, Camiel J. F.
AU - Rossin, Elizabeth J.
N1 - Publisher Copyright: © 2023 American Medical Association. All rights reserved.
PY - 2023/5/18
Y1 - 2023/5/18
N2 - Importance: Central 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. Objective: To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD. Design, Setting, and Participants: Using 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 Measures: Genome-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. Results: A total of 1176 patients with CSC and 526787 controls (312162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343461 controls were identified in the FinnGen study, 103 patients with CSC and 178573 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 Relevance: In 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.
AB - Importance: Central 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. Objective: To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD. Design, Setting, and Participants: Using 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 Measures: Genome-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. Results: A total of 1176 patients with CSC and 526787 controls (312162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343461 controls were identified in the FinnGen study, 103 patients with CSC and 178573 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 Relevance: In 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.
UR - http://www.scopus.com/inward/record.url?scp=85159757413&partnerID=8YFLogxK
U2 - https://doi.org/10.1001/jamaophthalmol.2023.0706
DO - https://doi.org/10.1001/jamaophthalmol.2023.0706
M3 - Article
C2 - 37079300
SN - 2168-6165
VL - 141
SP - 449
EP - 457
JO - JAMA ophthalmology
JF - JAMA ophthalmology
IS - 5
ER -