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  • Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
    Sanchez-Rodriguez, Elena; Liu, Lili; Khan, Atlas; Balderes, Olivia; Sanna-Cherchi, Simone; Bomback, Andrew S; Trimarchi, Hernan; Sprangers, Ben; Reich, Heather; Pei, York; Ravani, Pietro; Galesic, Kresimir; Tesar, Vladimir; Stengel, Benedicte; Canaud, Guillaume; Berthelot, Laureline; Monteiro, Renato; Nelson, Raoul; Wyatt, Robert J; Smoyer, William; Samhar, Al-Akash; Sreedharan, Raji; Selewski, David; Davis, Keefe; Kallash, Mahmoud; Ranch, Daniel; Akchurin, Oleh; Goumenos, Dimitrios; Kovacs, Tibor; Amoroso, Antonio; Barlassina, Cristina; Boer, Emanuela; Bono, Luisa; Caridi, Gianluca; Lugani, Francesca; Ghiggeri, GianMarco; Coppo, Rosanna; Esposito, Vittoria; Polci, Rosaria; Frasca, Giovanni; Mitrotti, Adele; Magnano, Andrea; Marcantoni, Carmelita; Messa, Piergiorgio; Mignani, Renzo; Ponticelli, Claudio; Roccatello, Dario; Salvadori, Maurizio; Savoldi, Silvana; Spotti, Donatella; Izzi, Claudia; Florczak, Michał; Krata, Natalia; Pączek, Leszek; Mizerska-Wasiak, Malgorzata; Durlik, Magdalena; Sikora, Przemyslaw; Zaniew, Marcin; Kuzmiuk-Glembin, Izabella; Bullo-Piontecka, Barbara; Dębska-Slizien, Alicja; Miklaszewska, Monika; Szczepańska, Maria; Siniewicz-Luzeńczyk, Katarzyna; Tkaczyk, Marcin; Kwella, Norbert; Drożdż, Dorota; Habura, Ireneusz; Prikhodina, Larisa; Cotsapas, Chris; Wijmenga, Cisca; Annese, Vito; Parameswaran, Sreeja; Kottyan, Leah; Suzuki, Hitoshi; Narita, Ichiei; Goto, Shin; Lee, Hajeong; Kim, Dong Ki; Kim, Yon Su; Park, Jin-Ho; Cho, BeLong; Van Wijk, Ans; Huerta, Ana; Ballarin, Jose; Mani, Laila-Yasmin; Caliskan, Yasar; Barratt, Jonathan; Kalra, Philip A; Gale, Daniel P; Rauen, Thomas; Schlosser, Pascal; Eckardt, Kai-Uwe; Chen, Nan; Lifton, Richard P; Ionita-Laza, Iuliana; Julian, Bruce A; Novak, Jan; Scolari, Francesco; Zhang, Hong

    Nature genetics, 07/2023, Letnik: 55, Številka: 7
    Journal Article

    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.

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