: 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 define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy / 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. - In: NATURE GENETICS. - ISSN 1546-1718. - 55:7(2023), pp. 1091-1105. [10.1038/s41588-023-01422-x]

Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Sanna-Cherchi, Simone;Fiaccadori, Enrico;Amoroso, Antonio;Bodria, Monica;Pisani, Isabella;Magnano, Andrea;Santoro, Domenico;Alberici, Federico;
2023-01-01

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.
2023
Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy / 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. - In: NATURE GENETICS. - ISSN 1546-1718. - 55:7(2023), pp. 1091-1105. [10.1038/s41588-023-01422-x]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2953021
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