학술논문
Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
Document Type
Original Paper
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. 55(7):1091-1105
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
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, TNFRSF13B and 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.
Genome-wide association analyses identify 30 risk loci for IgA nephropathy. Functional annotations of putative causal genes converge on inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.
Genome-wide association analyses identify 30 risk loci for IgA nephropathy. Functional annotations of putative causal genes converge on inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.