Genome-wide association study of anterior uveitis

Fredrika Koskimäki; Oona Ahokas; Risto Kajanne; Krista-Roberta Saviauk; Abdelrahman Elnahas; Anu Reigo; Kadri Reis; Tõnu Esko; Priit Palta; Sanna Leinonen; Johannes Kettunen; Johanna Liinamaa; Minna K Karjalainen; Ville Saarela; Estonian Biobank Research Team Consortium; FinnGen Consortium; Estonian Biobank Research Team Consortium authors

doi:10.1136/bjo-2024-326037

Genome-wide association study of anterior uveitis

Br J Ophthalmol. 2024 Dec 27:bjo-2024-326037. doi: 10.1136/bjo-2024-326037. Online ahead of print.

Authors

Fredrika Koskimäki¹, Oona Ahokas^{2

3}, Risto Kajanne⁴, Krista-Roberta Saviauk⁵, Abdelrahman Elnahas⁶, Anu Reigo⁶, Kadri Reis⁶, Tõnu Esko⁶, Priit Palta⁶, Sanna Leinonen⁷, Johannes Kettunen^{8

9}, Johanna Liinamaa², Minna K Karjalainen^{10

11}, Ville Saarela²; Estonian Biobank Research Team Consortium; FinnGen Consortium; Estonian Biobank Research Team Consortium authors

Collaborators

Andres Metspalu, Lili Milani, Reedik Mägi, Mari Nelis, Georgi Hudjashov, Tõnu Esko, Krista-Roberta Saviauk, Aarno Palotie, Mark Daly, Bridget Riley-Gills, Howard Jacob, Dirk Paul, Slavé Petrovski, Chia-Yen Chen, Sally John, George Okafo, Robert Plenge, Joseph Maranville, Mark McCarthy, Rion Pendergrass, Margaret G Ehm, Kirsi Auro, Simonne Longerich, Anders Mälarstig, Anna Vlahiotis, Katherine Klinger, Clement Chatelain, Matthias Gossel, Karol Estrada, Robert Graham, Dawn Waterworth, Chris O'Donnell, Nicole Renaud, Tomi P Mäkelä, Jaakko Kaprio, Minna Ruddock, Petri Virolainen, Antti Hakanen, Terhi Kilpi, Markus Perola, Jukka Partanen, Taneli Raivio, Jani Tikkanen, Raisa Serpi, Tarja Laitinen, Veli-Matti Kosma, Jari Laukkanen, Marco Hautalahti, Outi Tuovila, Raimo Pakkanen, Jeffrey Waring, Bridget Riley-Gillis, Fedik Rahimov, Ioanna Tachmazidou, Chia-Yen Chen, Zhihao Ding, Marc Jung, Hanati Tuoken, Shameek Biswas, Rion Pendergrass, David Pulford, Neha Raghavan, Adriana Huertas-Vazquez, Jae-Hoon Sul, Anders Mälarstig, Xinli Hu, Åsa Hedman, Katherine Klinger, Jonathan Chung, Jonas Zierer, Mari Niemi, Samuli Ripatti, Johanna Schleutker, Markus Perola, Mikko Arvas, Olli Carpén, Reetta Hinttala, Johannes Kettunen, Arto Mannermaa, Katriina Aalto-Setälä, Mika Kähönen, Jari Laukkanen, Johanna Mäkelä, Reetta Kälviäinen, Valtteri Julkunen, Hilkka Soininen, Anne Remes, Mikko Hiltunen, Jukka Peltola, Minna Raivio, Pentti Tienari, Juha Rinne, Roosa Kallionpää, Juulia Partanen, Adam Ziemann, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Heiko Runz, Sanni Lahdenperä, Shameek Biswas, Natalie Bowers, Edmond Teng, Rion Pendergrass, Fanli Xu, David Pulford, Kirsi Auro, Laura Addis, John Eicher, Qingqin S Li, Karen He, Ekaterina Khramtsova, Neha Raghavan, Martti Färkkilä, Jukka Koskela, Sampsa Pikkarainen, Airi Jussila, Katri Kaukinen, Timo Blomster, Mikko Kiviniemi, Markku Voutilainen, Mark Daly, Jeffrey Waring, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, Tim Lu, Linda McCarthy, Amy Hart, Meijian Guan, Jason Miller, Kirsi Kalpala, Melissa Miller, Xinli Hu, Kari Eklund, Antti Palomäki, Pia Isomäki, Laura Pirilä, Oili Kaipiainen-Seppänen, Johanna Huhtakangas, Nina Mars, Jeffrey Waring, Fedik Rahimov, Apinya Lertratanakul, Nizar Smaoui, Anne Lehtonen, Coralie Viollet, Marla Hochfeld, Jorge Esparza Gordillo, Kirsi Auro, Fabiana Farias, Kirsi Kalpala, Nan Bing, Xinli Hu, Tarja Laitinen, Margit Pelkonen, Paula Kauppi, Hannu Kankaanranta, Terttu Harju, Riitta Lahesmaa, Nizar Smaoui, Coralie Viollet, Susan Eaton, Hubert Chen, Rion Pendergrass, Natalie Bowers, Joanna Betts, Kirsi Auro, Rajashree Mishra, Majd Mouded, Debby Ngo, Teemu Niiranen, Felix Vaura, Veikko Salomaa, Kaj Metsärinne, Jenni Aittokallio, Mika Kähönen, Jussi Hernesniemi, Daniel Gordin, Juha Sinisalo, Marja-Riitta Taskinen, Tiinamaija Tuomi, Timo Hiltunen, Jari Laukkanen, Amanda Elliott, Mary Pat Reeve, Sanni Ruotsalainen, Dirk Paul, Audrey Chu, Kirsi Auro, Dermot Reilly, Mike Mendelson, Jaakko Parkkinen, Melissa Miller, Tuomo Meretoja, Heikki Joensuu, Olli Carpén, Johanna Mattson, Eveliina Salminen, Annika Auranen, Peeter Karihtala, Päivi Auvinen, Klaus Elenius, Johanna Schleutker, Esa Pitkänen, Mark Daly, Relja Popovic, Bridget Riley-Gillis, Anne Lehtonen, Margarete Fabre, Jennifer Schutzman, Diptee Kulkarni, Kirsi Auro, Alessandro Porello, Andrey Loboda, Heli Lehtonen, Stefan McDonough, Sauli Vuoti, Kai Kaarniranta, Joni A Turunen, Terhi Ollila, Hannu Uusitalo, Juha Karjalainen, Esa Pitkänen, Mengzhen Liu, Heiko Runz, Stephanie Loomis, Erich Strauss, Hao Chen, Kaisa Tasanen, Laura Huilaja, Katariina Hannula-Jouppi, Teea Salmi, Sirkku Peltonen, Leena Koulu, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, David Choy, Rion Pendergrass, Dawn Waterworth, Kirsi Kalpala, Ying Wu, Pirkko Pussinen, Aino Salminen, Tuula Salo, David Rice, Pekka Nieminen, Ulla Palotie, Maria Siponen, Liisa Suominen, Päivi Mäntylä, Ulvi Gursoy, Vuokko Anttonen, Kirsi Sipilä, Rion Pendergrass, Hannele Laivuori, Venla Kurra, Laura Kotaniemi-Talonen, Oskari Heikinheimo, Ilkka Kalliala, Lauri Aaltonen, Varpu Jokimaa, Johannes Kettunen, Marja Vääräsmäki, Outi Uimari, Laure Morin-Papunen, Maarit Niinimäki, Terhi Piltonen, Katja Kivinen, Elisabeth Widen, Taru Tukiainen, Mary Pat Reeve, Mark Daly, Niko Välimäki, Eija Laakkonen, Jaakko Tyrmi, Heidi Silven, Eeva Sliz, Riikka Arffman, Susanna Savukoski, Triin Laisk, Natalia Pujol, Mengzhen Liu, Bridget Riley-Gillis, Rion Pendergrass, Janet Kumar, Kirsi Auro, Iiris Hovatta, Chia-Yen Chen, Erkki Isometsä, Hanna Ollila, Jaana Suvisaari, Antti Mäkitie, Argyro Bizaki-Vallaskangas, Sanna Toppila-Salmi, Tytti Willberg, Elmo Saarentaus, Antti Aarnisalo, Eveliina Salminen, Elisa Rahikkala, Johannes Kettunen, Kristiina Aittomäki, Fredrik Åberg, Mitja Kurki, Samuli Ripatti, Mark Daly, Juha Karjalainen, Aki Havulinna, Juha Mehtonen, Priit Palta, Shabbeer Hassan, Pietro Della Briotta Parolo, Wei Zhou, Mutaamba Maasha, Shabbeer Hassan, Susanna Lemmelä, Manuel Rivas, Aarno Palotie, Aoxing Liu, Arto Lehisto, Andrea Ganna, Vincent Llorens, Hannele Laivuori, Taru Tukiainen, Mary Pat Reeve, Henrike Heyne, Joel Rämö, Elmo Saarentaus, Hanna Ollila, Rodos Rodosthenous, Satu Strausz, Tuula Palotie, Kimmo Palin, Javier Garcia-Tabuenca, Harri Siirtola, Tuomo Kiiskinen, Jiwoo Lee, Kristin Tsuo, Amanda Elliott, Kati Kristiansson, Mikko Arvas, Kati Hyvärinen, Jarmo Ritari, Olli Carpén, Johannes Kettunen, Katri Pylkäs, Eeva Sliz, Minna Karjalainen, Tuomo Mantere, Eeva Kangasniemi, Sami Heikkinen, Arto Mannermaa, Eija Laakkonen, Nina Pitkänen, Samuel Lessard, Clément Chatelain, Lila Kallio, Tiina Wahlfors, Jukka Partanen, Eero Punkka, Raisa Serpi, Sanna Siltanen, Veli-Matti Kosma, Teijo Kuopio, Anu Jalanko, Huei-Yi Shen, Risto Kajanne, Mervi Aavikko, Helen Cooper, Denise Öller, Rasko Leinonen, Henna Palin, Malla-Maria Linna, Mitja Kurki, Juha Karjalainen, Pietro Della Briotta Parolo, Arto Lehisto, Juha Mehtonen, Wei Zhou, Masahiro Kanai, Mutaamba Maasha, Zhili Zheng, Hannele Laivuori, Aki Havulinna, Susanna Lemmelä, Tuomo Kiiskinen, L Elisa Lahtela, Mari Kaunisto, Elina Kilpeläinen, Oluwaseun Alexander Dada, Awaisa Ghazal, Anastasia Kytölä, Rigbe Weldatsadik, Sanni Ruotsalainen, Kati Donner, Timo P Sipilä, Anu Loukola, Päivi Laiho, Tuuli Sistonen, Essi Kaiharju, Markku Laukkanen, Elina Järvensivu, Sini Lähteenmäki, Lotta Männikkö, Regis Wong, Auli Toivola, Minna Brunfeldt, Hannele Mattsson, Kati Kristiansson, Susanna Lemmelä, Sami Koskelainen, Tero Hiekkalinna, Teemu Paajanen, Priit Palta, Shuang Luo, Tarja Laitinen, Mary Pat Reeve, Shanmukha Sampath Padmanabhuni, Marianna Niemi, Harri Siirtola, Javier Gracia-Tabuenca, Mika Helminen, Tiina Luukkaala, Iida Vähätalo, Jyrki Tammerluoto, Marco Hautalahti, Johanna Mäkelä, Sarah Smith, Tom Southerington, Petri Lehto

Affiliations

¹ Department of Ophthalmology and Medical Research Center, Oulu University Hospital; Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland [email protected].
² Department of Ophthalmology and Medical Research Center, Oulu University Hospital; Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland.
³ Department of Mathematical Sciences, University of Oulu, Oulu, Finland.
⁴ FinnGen, Helsinki, Finland.
⁵ Estonian Biobank Research Team, Estonia, Estonia.
⁶ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁷ Tays Eye Centre, Tampere University Hospital, Tampere, Finland.
⁸ Research Unit of Population Health, Faculty of Medicine, University of Oulu; Biocenter Oulu, University of Oulu, Oulu, Finland.
⁹ Finnish Institute for Health and Welfare (THL), Helsinki, Finland.
¹⁰ Research Unit of Population Health, Faculty of Medicine, University of Oulu; Northern Finland Birth Cohorts, Arctic Biobank, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹¹ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.

PMID: 39732499
DOI: 10.1136/bjo-2024-326037

Abstract

Background/aims: The purpose of this study is to define genetic factors associated with anterior uveitis through genome-wide association study (GWAS).

Methods: In this GWAS meta-analysis, we combined data from the FinnGen, Estonian Biobank and UK Biobank with a total of 12 205 anterior uveitis cases and 917 145 controls. We performed a phenome-wide association study (PheWAS) to investigate associations across phenotypes and traits. We also evaluated genetic correlations of anterior uveitis.

Results: We identified six anterior uveitis-associated loci. Genome-wide significant (p<5 × 10^-8) associations were identified for the first time at three loci (innate immunity activator (INAVA), nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 and nitric oxide synthase 2). We detected associations at three loci previously reported to be associated with uveitis (endoplasmic reticulum aminopeptidase 1 (ERAP1), the trinucleotide repeat containing 18 (TNRC18) and the HLA region) and also replicated associations at two loci previously associated with acute anterior uveitis (IL23R and HDAC2-AS2). In PheWAS, we further detected that lead single nucleotide polymorphisms (SNPs) at three of the anterior uveitis-associated loci (ERAP1, INAVA and TNRC18) are associated with other immunity-related phenotypes, including ankylosing spondylitis and inflammatory bowel disease. Additionally, we detected a moderate genetic correlation between anterior uveitis and inflammatory bowel disease (r_g =0.39, p=8 × 10^-5).

Conclusion: We identified six anterior uveitis-associated loci, including three novel loci with genome-wide significance. Our findings deepen our understanding of the genetic basis of anterior uveitis and the genetic connections between anterior uveitis and immune-related disorders, providing a foundation for further research and potential therapeutic interventions.

Keywords: Genetics; Inflammation; Uveitis.