Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy

Yuki Mori; Masahiro Miyake; Yoshikatsu Hosoda; Akiko Miki; Ayako Takahashi; Yuki Muraoka; Manabu Miyata; Takehiro Sato; Hiroshi Tamura; Sotaro Ooto; Ryo Yamada; Kenji Yamashiro; Makoto Nakamura; Atsushi Tajima; Masao Nagasaki; Shigeru Honda; Akitaka Tsujikawa

doi:10.1016/j.ophtha.2022.04.018

Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy

Ophthalmology. 2022 Sep;129(9):1034-1042. doi: 10.1016/j.ophtha.2022.04.018. Epub 2022 Apr 29.

Authors

Yuki Mori¹, Masahiro Miyake², Yoshikatsu Hosoda³, Akiko Miki⁴, Ayako Takahashi⁵, Yuki Muraoka⁵, Manabu Miyata⁵, Takehiro Sato⁶, Hiroshi Tamura⁵, Sotaro Ooto⁵, Ryo Yamada⁷, Kenji Yamashiro⁸, Makoto Nakamura⁴, Atsushi Tajima⁶, Masao Nagasaki⁷, Shigeru Honda⁹, Akitaka Tsujikawa⁵

Affiliations

¹ Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
² Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: miyakem@kuhp.kyoto-u.ac.jp.
³ Department of Ophthalmology, Osaka Red-Cross Hospital, Osaka, Japan.
⁴ Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.
⁵ Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁶ Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
⁷ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁸ Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University, Nankoku City, Kochi, Japan.
⁹ Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan.

PMID: 35490733
DOI: 10.1016/j.ophtha.2022.04.018

Abstract

Purpose: To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC).

Design: Genome-wide survival analysis using a longitudinal cohort study.

Participants: We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography.

Methods: We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values < 1.0 × 10^-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis.

Main outcome measures: The association between SNPs and MNV development in patients with CSC.

Results: Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]_meta, 3.63; P_meta = 5.76 × 10^-9). Among previously reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR, 0.39, P = 2.55 × 10^-4), COL4A3 rs4276018 (HR, 0.26, P = 1.56 × 10^-3), and B3GALTL rs9564692 (HR, 0.56, P = 8.30 × 10^-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of 8 pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport.

Conclusions: ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

Keywords: Central serous chorioretinopathy; Choroidal neovascularization; Genome-wide association study; Macular neovascularization; Survival analysis.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Central Serous Chorioretinopathy* / complications
Central Serous Chorioretinopathy* / diagnosis
Central Serous Chorioretinopathy* / genetics
Choroid
Choroidal Neovascularization* / complications
Choroidal Neovascularization* / diagnosis
Choroidal Neovascularization* / genetics
Eye Diseases* / complications
Fluorescein Angiography
Genetic Predisposition to Disease
Humans
Longitudinal Studies
Macular Degeneration* / genetics
Neovascularization, Pathologic
Survival Analysis
Tomography, Optical Coherence