Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
Archive ouverte
Kiryluk, Krzysztof | Sanchez-Rodriguez, Elena | Zhou, Xujie | Zanoni, Francesca | Liu, Lili | Mladkova, Nikol | Khan, Atlas | Marasa, Maddalena | Zhang, Junying | Balderes, Olivia | Sanna-Cherchi, Simone | Bomback, Andrew S. | Canetta, Pietro A. | Appel, Gerald B. | Radhakrishnan, Jai | Trimarchi, Hernán M. | Sprangers, Ben | Cattran, Daniel Cheyne | Reich, Heather N. | Pei, York P.C. | Ravani, Pietro | Galesic, Krešimir | Maixnerova, Dita | Tesar, Vladimír | Stengel, Bénédicte Né Dicte | Metzger, Marie | Canaud, Guillaume | Maillard, Nicolas | Berthoux, Francçois Claude | Berthelot, Laureline | Pillebout, Évangéline | Monteiro, Renato C. | Nelson, Raoul D. | Wyatt, Robert J. | Smoyer, William E. | Mahan, John D. | Samhar, Al Akash | Hidalgo, Guillermo | Quiroga, Alejandro | Weng, Patricia L. | Sreedharan, Rajasree | Selewski, David T. | Davis, Keefe | Kallash, Mahmoud | Vasylyeva, Tetyana L. | Rheault, Michelle N. | Chishti, Aftab S. | Ranch, Daniel | Wenderfer, Scott E. | Samsonov, Dmitry V. | Claes, Donna J. | Akchurin, Oleh M. | Goumenos, Dimitrios S. | Stangou, Maria | Nagy, Judit M. | Kovacs, Tibor | Fiaccadori, Enrico | Amoroso, Antonio | Barlassina, Cristina | Cusi, Daniele M. | del Vecchio, Lucia | Battaglia, Giovanni Giorgio | Bodria, Monica | Boer, Emanuela | Bono, Luisa | Boscutti, Giuliano | Caridi, Gianluca | Lugani, Francesca | Ghiggeri, G. M. | Coppo, Rosanna | Peruzzi, Licia | Esposito, Vittoria | Esposito, Ciro | Feriozzi, Sandro | Polci, Rosaria | Frasca, Giovanni Maria | 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 E. | Roccatello, Dario | Salvadori, Maurizio O. | Salvi, Erika | 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, Małgorzata | Mizerska-Wasiak, Małgorzata | Perkowska-Ptasińska, Agnieszka | Bączkowska, Teresa | Durlik, Magdalena | Pawlaczyk, Krzysztof | Sikora, Przemysław | Zaniew, Marcin | Kaminska, Dorota | Krajewska, Magdalena | Kuzmiuk-Glembin, Izabella | Heleniak, Zbigniew T. | Bullo-Piontecka, Barbara | Liberek, Tomasz | Dębska-Slizien, Alicja M. | 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, L. S. | van Heel, David A. | Fontaine, Bertrand | Cotsapas, Chris J. | Wijmenga, Cisca | Franke, Andre | Annese, Vito | Gregersen, Peter K. | Parameswaran, Sreeja | Weirauch, Matthew T. | Kottyan, Leah C. | Harley, John Barker | Suzuki, Hitoshi | Narita, Ichiei | Goto, Shin | Lee, Hajeong | Kim, Dongki | Kim, Yon Su | Park, Jinho | Cho, Be-Long | Choi, Murim | van Wijk, Ans | Huerta, Ana | Ars, Elisabet | Ballarin, José A. | Lundberg, Sigrid | Vogt, Bruno | Mani, Laila Yasmin | Caliskan, Yaśar Kerem | Barratt, Jonathan | Abeygunaratne, Thilini | Kalra, Philip A. | Gale, Daniel Philip | Panzer, Ulf | Rauen, Thomas | Floege, Jürgen | Schlosser, Pascal | Ekici, Arif Bülent | 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.
Edité par
CCSD ; Nature Publishing Group -
International audience.
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.
