학술논문
Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
Document Type
Article
Author
Kiryluk, Krzysztof; Sanchez-Rodriguez, Elena; Zhou, Xu-Jie; Zanoni, Francesca; Liu, Lili; Mladkova, Nikol; Khan, Atlas; Marasa, Maddalena; Zhang, Jun Y.; Balderes, Olivia; Sanna-Cherchi, Simone; Bomback, Andrew S.; Canetta, Pietro A.; Appel, Gerald B.; Radhakrishnan, Jai; Trimarchi, Hernan; Sprangers, Ben; Cattran, Daniel C.; Reich, Heather; Pei, York; Ravani, Pietro; Galesic, Kresimir; Maixnerova, Dita; Tesar, Vladimir; Stengel, Benedicte; Metzger, Marie; Canaud, Guillaume; Maillard, Nicolas; Berthoux, Francois; Berthelot, Laureline; Pillebout, Evangeline; Monteiro, Renato; Nelson, Raoul; Wyatt, Robert J.; Smoyer, William; Mahan, John; Samhar, Al-Akash; Hidalgo, Guillermo; Quiroga, Alejandro; Weng, Patricia; Sreedharan, Raji; Selewski, David; Davis, Keefe; Kallash, Mahmoud; Vasylyeva, Tetyana L.; Rheault, Michelle; Chishti, Aftab; Ranch, Daniel; Wenderfer, Scott E.; Samsonov, Dmitry; Claes, Donna J.; Akchurin, Oleh; Goumenos, Dimitrios; Stangou, Maria; Nagy, Judit; Kovacs, Tibor; Fiaccadori, Enrico; Amoroso, Antonio; Barlassina, Cristina; Cusi, Daniele; Del Vecchio, Lucia; Battaglia, Giovanni Giorgio; Bodria, Monica; Boer, Emanuela; Bono, Luisa; Boscutti, Giuliano; Caridi, Gianluca; Lugani, Francesca; Ghiggeri, GianMarco; Coppo, Rosanna; Peruzzi, Licia; Esposito, Vittoria; Esposito, Ciro; Feriozzi, Sandro; Polci, Rosaria; Frasca, Giovanni; Galliani, Marco; Garozzo, Maurizio; Mitrotti, Adele; Gesualdo, Loreto; Granata, Simona; Zaza, Gianluigi; Londrino, Francesco; Magistroni, Riccardo; Pisani, Isabella; Magnano, Andrea; Marcantoni, Carmelita; Messa, Piergiorgio; Mignani, Renzo; Pani, Antonello; Ponticelli, Claudio; Roccatello, Dario; Salvadori, Maurizio; Salvi, Erica; Santoro, Domenico; Gembillo, Guido; Savoldi, Silvana; Spotti, Donatella; Zamboli, Pasquale; Izzi, Claudia; Alberici, Federico; Delbarba, Elisa; Florczak, Michał; Krata, Natalia; Mucha, Krzysztof; Pączek, Leszek; Niemczyk, Stanisław; Moszczuk, Barbara; Pańczyk-Tomaszewska, Malgorzata; Mizerska-Wasiak, Malgorzata; Perkowska-Ptasińska, Agnieszka; Bączkowska, Teresa; Durlik, Magdalena; Pawlaczyk, Krzysztof; Sikora, Przemyslaw; Zaniew, Marcin; Kaminska, Dorota; Krajewska, Magdalena; Kuzmiuk-Glembin, Izabella; Heleniak, Zbigniew; Bullo-Piontecka, Barbara; Liberek, Tomasz; Dębska-Slizien, Alicja; Hryszko, Tomasz; Materna-Kiryluk, Anna; Miklaszewska, Monika; Szczepańska, Maria; Dyga, Katarzyna; Machura, Edyta; Siniewicz-Luzeńczyk, Katarzyna; Pawlak-Bratkowska, Monika; Tkaczyk, Marcin; Runowski, Dariusz; Kwella, Norbert; Drożdż, Dorota; Habura, Ireneusz; Kronenberg, Florian; Prikhodina, Larisa; van Heel, David; Fontaine, Bertrand; Cotsapas, Chris; Wijmenga, Cisca; Franke, Andre; Annese, Vito; Gregersen, Peter K.; Parameswaran, Sreeja; Weirauch, Matthew; Kottyan, Leah; Harley, John B.; Suzuki, Hitoshi; Narita, Ichiei; Goto, Shin; Lee, Hajeong; Kim, Dong Ki; Kim, Yon Su; Park, Jin-Ho; Cho, BeLong; Choi, Murim; Van Wijk, Ans; Huerta, Ana; Ars, Elisabet; Ballarin, Jose; Lundberg, Sigrid; Vogt, Bruno; Mani, Laila-Yasmin; Caliskan, Yasar; Barratt, Jonathan; Abeygunaratne, Thilini; Kalra, Philip A.; Gale, Daniel P.; Panzer, Ulf; Rauen, Thomas; Floege, Jürgen; Schlosser, Pascal; Ekici, Arif B.; Eckardt, Kai-Uwe; Chen, Nan; Xie, Jingyuan; Lifton, Richard P.; Loos, Ruth J. F.; Kenny, Eimear E.; Ionita-Laza, Iuliana; Köttgen, Anna; Julian, Bruce A.; Novak, Jan; Scolari, Francesco; Zhang, Hong; Gharavi, Ali G.
Source
Nature Genetics; July 2023, Vol. 55 Issue: 7 p1091-1105, 15p
Subject
Language
ISSN
10614036; 15461718
Abstract
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13Band FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.