DOI: 10.1001/jamaophthalmol.2026.4427 ISSN: 2168-6165

Genome-Wide Association Study Meta-Analysis of Central Serous Chorioretinopathy

Liyin Chen, Soo Hyun Francesca Kim, Buu Truong, Joel T. Rämö, Bryan R. Gorman, Elon H. C. van Dijk, Joost Brinks, Tiit Nikopensius, Seung Hoan Choi, Risto Kajanne, Juha Mehtonen, Kai Kaarniranta, Lucia Sobrin, Mitja Kurki, Suzanne Yzer, Wen-Chih Wu, Joni A. Turunen, Ayellet V. Segrè, Josep Maria Mercader, Alicia Huerta, Mark J. Daly, Aarno Palotie, Patrick T. Ellinor, Camiel J. F. Boon, Sudha K. Iyengar, Neal S. Peachey, Pradeep Natarajan, Elizabeth J. Rossin, , Bridget Riley-Gills, Howard Jacob, Coralie Viollet, Slavé Petrovski, Alix Berton, Santha Ramakrishnan, Ellen Tsai, Zhihao Ding, Emily Holzinger, Robert Plenge, Joseph Maranville, Mark McCarthy, Rion Pendergrass, Jonathan Davitte, Chia-Yen Chen, Melis Atalar Aksit, Anna Vlahiotis, Katherine Klinger, Clement Chatelain, Jorg Blankenstein, Karol Estrada, Robert Graham, Dawn Waterworth, Chris O´Donnell, Nicole Renaud, Tomi P. Mäkelä, Jaakko Kaprio, Minna Ruddock, Lila Kallio, Antti Hakanen, Terhi Kilpi, Markus Perola, Jukka Partanen, Taneli Raivio, Eero Punkka, Teija Kekonen, Raisa Serpi, Kati Kristiansson, Sanna Siltanen, Veli-Matti Kosma, Arto Mannermaa, Jari Laukkanen, Tiina Jokela, Mervi Ahlroth, Johanna Mäkelä, Outi Tuovila, Jeffrey Waring, Bridget Riley-Gillis, Fedik Rahimov, Ioanna Tachmazidou, Marc Jung, Hanati Tuoken, Shameek Biswas, Benjamin Sun, Neha Raghavan, Jae-Hoon Sul, Xinli Hu, Ma´en Obeidat, Jonathan Chung, Jonas Zierer, Mari Niemi, Samuli Ripatti, Johanna Schleutker, Tiina Wahlfors, Mikko Arvas, Olli Carpén, Reetta Hinttala, Johannes Kettunen, Katriina Aalto-Setälä, Mika Kähönen, Hanna Kujala, Triin Laisk, Natalia Pujol, Veikko Salomaa, Jaana Suvisaari, Satu Koskela, Jouni Lauronen, Kristiina Aittomäki, Pirkko Pussinen, Tuomo Meretoja, Heikki Joensuu, Peeter Karihtala, Emma Juuri, Aino Salminen, Tuula Salo, David Rice, Pekka Nieminen, Ulla Palotie, Fredrik Åberg, Daniel Gordin, Patrik Finne, Minna Raivio, Pentti Tienari, Martti Färkkilä, Jukka Koskela, Sampsa Pikkarainen, Kari Eklund, Paula Kauppi, Juha Sinisalo, Marja-Riitta Taskinen, Tiinamaija Tuomi, Timo Hiltunen, Johanna Mattson, Eveliina Salminen, Terhi Ollila, Katariina Hannula-Jouppi, Oskari Heikinheimo, Ilkka Kalliala, Lauri Aaltonen, Erkki Isometsä, Antti Aarnisalo, Ilkka Immonen, Salla Ranta, Filip Scheperjans, Felix Vaura, Nina Mars, Esa Pitkänen, Hannele Laivuori, Tuomo Kiiskinen, Katja Kivinen, Elisabeth Widen, Taru Tukiainen, Hanna Ollila, Elmo Saarentaus, Anne Kerola, Eero Vuoksimaa, Joni Lindbohm, Zhiyu Yang, Matthew Sampson, Michelle McNulty, Aoxing Liu, Austin Argentieri, Amanda Elliott, Elisa Rahikkala, Kirsi Sipilä, Valtteri Julkunen, Ville Leinonen, Sanna Toppila-Salmi, Mikko Hiltunen, Eino Solje, Hannu Kankaanranta, Antti Mäkitie, Iiris Hovatta, Niko Välimäki, Minttu Marttila, Anne Portaankorva, Eija Laakkonen, Heidi Silven, Eeva Sliz, Riikka Arffman, Susanna Savukoski, Riitta Kaarteenaho, Minna Karjalainen, Jaakko Tyrmi, Laura Kuusalo, Laura Pirilä, Tapio Hellman, Matti Vuori, Teemu Niiranen, Timo Blomster, Johanna Huhtakangas, Terttu Harju, Kaisa Tasanen, Laura Huilaja, Vuokko Anttonen, Marja Vääräsmäki, Outi Uimari, Laure Morin-Papunen, Maarit Niinimäki, Terhi Piltonen, Reetta Kälviäinen, Hilkka Soininen, Mikko Kiviniemi, Oili Kaipiainen-Seppänen, Margit Pelkonen, Päivi Auvinen, Maria Siponen, Liisa Suominen, Päivi Mäntylä, Jukka Peltola, Airi Jussila, Katri Kaukinen, Pia Isomäki, Jussi Hernesniemi, Annika Auranen, Hannu Uusitalo, Teea Salmi, Venla Kurra, Laura Kotaniemi-Talonen, Argyro Bizaki-Vallaskangas, Juha Rinne, Roosa Kallionpää, Markku Voutilainen, Antti Palomäki, Riitta Lahesmaa, Kaj Metsärinne, Jenni Aittokallio, Klaus Elenius, Sirkku Peltonen, Leena Koulu, Ulvi Gursoy, Varpu Jokimaa, Tytti Willberg, Adam Ziemann, Nizar Smaoui, Anne Lehtonen, Apinya Lertratanakul, Relja Popovic, Mengzhen Liu, Anneke Den Hollander, Jan Freudenberg, Britney Milkovich, Andrew Blumenfeld, Tushar Kumar, Dirk Paul, Bram Prins, Eleanor Wheeler, Kousik Kundu, Santosh Atanur, Andrew Lowe, Thomas Spargo, Oliver Burren, Margarete Fabre, Fabio Baschiera, Hans van Leeuwen, Himanshu Manchanda, Karl Heilbron, Martin Rao, Nicole Schmidt, Samu Kurki, Johanna Mielke, Juho Immonen, Thomas Battram, Tobias Hogrebe, Susan Eaton, Ketian Yu, Stephanie Loomis, Coro Paisan-Ruiz, Elke Markert, Frank Li, Yao Hu, Christoph Ogris, Eric Simon, Julio Cesar Bolivar Lopez, Monika Frysz, Marla Hochfeld, Cara Carty, Michael Turchin, Neelakshi Jog, Corneliu Bodea, Janie Shelton, Chen Li, Kritika Singh, Peng Jiang, Elena Sanchez, Lilith Moss, Zijie Zhao, Anna Podgornaia, Natalie Bowers, Edmond Teng, Tim Lu, Hubert Chen, Jennifer Schutzman, Erich Strauss, Hao Chen, David Choy, Brian Yaspan, Cameron Adams, Michael Rothenberg, Sergio Dellepiane, Anubha Mahajan, Michael Holmes, Diana Chang, Tushar Bhangale, Fanli Xu, Laura Addis, John Eicher, Linda McCarthy, Jorge Esparza Gordillo, Joanna Betts, Rajashree Mishra, Audrey Chu, Diptee Kulkarni, Janet Kumar, Charli Harlow, Lea Sarow-Blat, Diana L. Cousminer, Jagtar Nijjar, Jessica Chao, Michal Magid, Shashank Jariwala, Chris Floyd, Dan Swerdlow, Erding Hu, Prerak Desai, Stephen Haddad, Damien Croteau-Chonka, Billy Fahy, Paola Bronson, Kirsi Auro, David Pulford, Sauli Vuoti, Dermot Reilly, Karen He, Ekaterina Khramtsova, Amy Hart, Meijian Guan, Alessandro Porello, P. Dunnmon, Sara Gale, Brice Keyes, John Kwon, Jonathan Sherlock, Matt Loza, Chris Whelan, W Galpern, Yanfei Zhang, Mona Selej, Abolfazl Doostparast Torshizi, Qingqin S Li, Sahar Mozzafari, Christopher Deboever, Jason Miller, Fabiana Farias, Andrey Loboda, Jorge Del-aguila, Elisabeth Vollmann, Jozsef Karman, Julie Fiore, Rajesh Kamath, Andrei Popescu, Delphine Fagegaltier, Travis Barr, Aristide Merola, Oliver Freeman, Simonne Longerich, Enrico Ferrero, Nikos Patsopoulos, Nancy Finkel, Sabina Pfister, Shola Richards, Katherine Mccauley, Xiaobo Xia, Mike Mendelson, Majd Mouded, Debby Ngo, Kirsi Kalpala, Melissa Miller, Nan Bing, Jaakko Parkkinen, Heli Lehtonen, Stefan McDonough, Ying Wu, Erin Macdonald-Dunlop, Jessica Chung, Michael McLean, Joshua Chiou, Hye In Kim, Sivakumar Pitchumani, Sumedha Jassal, Madhurima Saxena, Catherine O’Riordan, Samuel Lessard, Suzanne Jacobs, Hamid Mattoo, David Habiel, Guanling Huan, Anu Jalanko, Mervi Aavikko, Helen Cooper, Denise Öller, Tarja Laitinen, Rodos Rodosthenous, Sofia Kuitunen, Juha Karjalainen, Pietro Della Briotta Parolo, Arto Lehisto, Reza Jabal, Mutaamba Maasha, Sanni Ruotsalainen, Samuel Jones, Raymond Walters, Paavo Häppölä, Topi Paavilainen, L. Elisa Lahtela, Johanna Paltta, Juulia Partanen, Olli K. Pietiläinen, Veera Timonen, Mari Kaunisto, Elina Kilpeläinen, Tianduanyi Wang, Timo P. Sipilä, Oluwaseun Alexander Dada, Awaisa Ghazal, Rigbe Weldatsadik, Jaska Uimonen, Kati Donner, Anu Loukola, Päivi Laiho, Susanna Lemmelä, Teemu Paajanen, Arto Pietilä, Aki Havulinna, Auli Toivola, Kristina Zguro, Mary Pat Reeve, Shanmukha Sampath Padmanabhuni, Harri Siirtola, Javier Gracia-Tabuenca, Marika Kaakinen, Shuang Luo, Vincent Llorens, Dawit Yohannes, Iina Laak, Pauli Wihuri, Tom Southerington, Meri Lähteenmäki
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Importance

The pathophysiology of central serous chorioretinopathy (CSC) remains incompletely understood, and there is ongoing debate regarding the origin of primary dysfunction.

Objective

To elucidate the genetic architecture of CSC and map susceptibility loci to specific ocular cell types and molecular pathways.

Design, Setting, and Participants

This genetic association study was a genome-wide association study (GWAS) meta-analysis aggregating data from 5 large biobank cohorts and included 2584 patients with CSC and 1 044 455 control participants of European ancestry. Cohort data were from July 1, 2010, to October 31, 2023; data analysis was performed from Febuary 2024 to January 2026. Post-GWAS functional mapping was performed using mendelian randomization, bayesian colocalization, and single-cell disease relevance scoring across human ocular tissue atlases. The relevance of the genetic findings was demonstrated by building a CSC genetic risk score and applying it to the UK Biobank (UKB).

Main Outcomes and Measures

Identification of risk loci reaching the genome-wide threshold, prioritized putative causal genes, enrichment of genetic risk within specific ocular tissues and cell types, and performance of a GRS in the independent UKB dataset.

Results

The meta-analysis identified 10 risk loci reaching the genome-wide threshold ( P  < 5 × 10 −8 ), including 3 novel loci ( TGFB1 , LINC00551 , and LOC105375630 ) and 7 replicated loci ( CFH , GATA5 , PREX1 , CD46 , NOTCH4, PTPRB, and TNFRSF10A ). Integrative post-GWAS analysis prioritized 10 genes, including TGFB1 , TNFRSF10A , and CFH, as likely causal effectors. Single-cell enrichment mapping revealed that CSC genetic risk is concentrated in scleral tissue ( P  < .001) and vascular endothelial cells ( P  < .001). Mendelian randomization pointed to circulating TGFB1 and TNFRSF10A levels as associated with CSC risk. A CSC genetic risk score applied in UKB revealed a higher frequency of CSC-relevant abnormalities on macular optical coherence tomography in participants in the top 1% of polygenic risk (18/109 [16.5%] vs 8/134 [6.0%]; difference, 10.5 percentage points; 95% CI, 2.6-19.1; adjusted odds ratio, 4.05; 95% CI, 1.65-10.87; P  = .002).

Conclusions and Relevance

Convergent genetic evidence supports CSC as a primary disorder of the sclera and choroidal vasculature with retinal pigment epithelium changes likely representing a downstream consequence. Integrative post-GWAS analysis pointed to complement regulation ( CFH, CD46 ), vascular integrity and endothelial cell signaling ( PTPRB, TNFRSF10A, NOTCH4, PREX1 ), and scleral extracellular matrix biology ( TGFB1 ) as important in CSC.

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