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GWAS defines pathogenic signaling pathways and prioritizes drug targets for IgA nephropathy

By Krzysztof Kiryluk, Elena Sanchez-Rodriguez, Xu-jie Zhou, Francesca Zanoni, Lili Liu, Nikol Mladkova, Atlas Khan, Maddalena Marasa, Jun-Ying Zhang, Olivia Balderes, Simone Sanna-Cherchi, Andrew S. Bomback, Pietro A. Canetta, Gerald B Appel, Jai Radhakrishnan, Hernan Trimarchi, Ben Sprangers, Daniel C Cattran, Heather Reich, York Pei, Pietro Ravani, Kresimir Galesic, Dita Maixnerova, Vladimir Tesar, Benedicte Stengel, Marie Metzger, Guillaume Canaud, Nicolas Maillard, Francois Berthoux, Laureline Berthelot, Evangeline Pillebout, Renato Monteiro, Raoul Nelson, Robert Wyatt, William Smoyer, John Mahan, Al-Akash Samhar, Guillermo Hidalgo, Alejandro Quiroga, Patricia Weng, Raji Sreedharan, David Selewski, Keefe Davis, Mahmoud Kallash, Tetyana L. Vasylyeva, Michelle Rheault, Aftab Chishti, Daniel Ranch, Scott E. Wenderfer, Dmitry Samsonov, Donna J. Claes, Akchurin Oleh, Dimitrios Goumenos, Maria Stangou, Judit Nagy, Tibor Kovacs, Enrico Fiaccadori, Antonio Amoroso, Cristina Barlassina, Daniele Cusi, Lucia Del Vecchio, Giovanni-Giorgio Battaglia, Monica Bodria, Emanuela Boer, Luisa Bono, Giuliano Boscutti, Gianluca Caridi, Francesca Lugani, GianMarco Ghiggeri, Rosanna Coppo, Licia Peruzzi, Vittoria Esposito, Ciro Esposito, Sandro Feriozzi, Rosaria Polci, Giovanni Frasca, Marco Galliani, Maurizio Garozzo, Adele Mitrotti, Loreto Gesualdo, Simona Granata, Gianluigi Zaza, Francesco Londrino, Riccardo Magistroni, Isabella Pisani, Andrea Magnano, Carmelita Marcantoni, Piergiorgio Messa, Renzo Mignani, Antonello Pani, Claudio Ponticelli, Dario Roccatello, Maurizio Salvadori, Erica Salvi, Domenico Santoro, Guido Gembillo, Silvana Savoldi, Donatella Spotti, Pasquale Zamboli, Claudia Izzi, Federico Alberici, Elisa Delbarba, Michal Florczak, Natalia Krata, Krzysztof Mucha, Leszek Paczek, Stanisaw Niemczyk, Barbara Moszczuk, Magorzata Panczyk-Tomaszewska, Malgorzata Mizerska-Wasiak, Agnieszka Perkowska-Ptasinska, Teresa Baczkowska, Magdalena Durlik, Krzysztof Pawlaczyk, Przemyslaw Sikora, Marcin Zaniew, Dorota Kaminska, Magdalena Krajewska, Izabella Kuzmiuk-Glembin, Zbigniew Heleniak, Barbara Bullo-Piontecka, Tomasz Liberek, Alicja Dbska-Slizien, Tomasz Hryszko, Anna Materna-Kiryluk, Monika Miklaszewska, Maria Szczepanska, Katarzyna Dyga, Edyta Machura, Katarzyna Siniewicz-Luzenczyk, Monika Pawlak-Bratkowska, Marcin Tkaczyk, Dariusz Runowski, Norbert Kwella, Dorota Drozdz, Ireneusz Habura, Florian Kronenberg, Larisa Prikhodina, David A van Heel, Bertrand Fontaine, Chris Cotsapas, Cisca Wijmenga, Andre Franke, Vito Annese, Peter K Gregersen, Sreeja Parameswaran, Matthew T Weirauch, Leah Kottyan, John B. Harley, Hitoshi Suzuki, Ichiei Narita, Shin Goto, Hajeong Lee, Dong-Ki Kim, Yon Su Kim, Jin-Ho Park, BeLong Cho, Murim Choi, Ans Van Wijk, Ana Huerta, Elisabet Ars, Jose Ballarin, Sigrid Lundberg, Bruno Vogt, Laila-Yasmin Mani, Yasar Caliskan, Jonathan Barratt, Thilini Abeygunaratne, Philip A Kalra, Daniel P Gale, Ulf Panzer, Thomas Rauen, Jurgen Floege, Pascal Schlosser, Arif B. Ekici, Kai-Uwe Eckardt, Nan Chen, Jingyuan Xie, Richard P Lifton, Ruth J.F. Loos, Eimear E. Kenny, Iuliana Ionita-Laza, Anna Kottgen, Bruce Julian, Jan Novak, Francesco Scolari, Hong Zhang, Ali G Gharavi

Posted 20 Nov 2021
medRxiv DOI: 10.1101/2021.11.19.21265383

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the 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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