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.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, K.; Sanchez-Rodriguez, E.; Zhou, X. J.; Zanoni, F.; Liu, L.; Mladkova, N.; Khan, A.; Marasa, M.; Zhang, J. Y.; Balderes, O.; Sanna-Cherchi, S.; Bomback, A. S.; Canetta, P. A.; Appel, G. B.; Radhakrishnan, J.; Trimarchi, H.; Sprangers, B.; Cattran, D. C.; Reich, H.; Pei, Y.; Ravani, P.; Galesic, K.; Maixnerova, D.; Tesar, V.; Stengel, B.; Metzger, M.; Canaud, G.; Maillard, N.; Berthoux, F.; Berthelot, L.; Pillebout, E.; Monteiro, R.; Nelson, R.; Wyatt, R. J.; Smoyer, W.; Mahan, J.; Samhar, A. A.; Hidalgo, G.; Quiroga, A.; Weng, P.; Sreedharan, R.; Selewski, D.; Davis, K.; Kallash, M.; Vasylyeva, T. L.; Rheault, M.; Chishti, A.; Ranch, D.; Wenderfer, S. E.; Samsonov, D.; Claes, D. J.; Akchurin, O.; Goumenos, D.; Stangou, M.; Nagy, J.; Kovacs, T.; Fiaccadori, E.; Amoroso, A.; Barlassina, C.; Cusi, D.; Del Vecchio, L.; Battaglia, G. G.; Bodria, M.; Boer, E.; Bono, L.; Boscutti, G.; Caridi, G.; Lugani, F.; Ghiggeri, G. M.; Coppo, R.; Peruzzi, L.; Esposito, V.; Esposito, C.; Feriozzi, S.; Polci, R.; Frasca, G.; Galliani, M.; Garozzo, M.; Mitrotti, A.; Gesualdo, L.; Granata, S.; Zaza, G.; Londrino, F.; Magistroni, R.; Pisani, I.; Magnano, A.; Marcantoni, C.; Messa, P.; Mignani, R.; Pani, A.; Ponticelli, C.; Roccatello, D.; Salvadori, M.; Salvi, E.; Santoro, D.; Gembillo, G.; Savoldi, S.; Spotti, D.; Zamboli, P.; Izzi, C.. - In: NATURE GENETICS. - ISSN 1061-4036. - 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

Magistroni R.;
2023

Abstract

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.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
55
7
1091
1105
Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy / Kiryluk, K.; Sanchez-Rodriguez, E.; Zhou, X. J.; Zanoni, F.; Liu, L.; Mladkova, N.; Khan, A.; Marasa, M.; Zhang, J. Y.; Balderes, O.; Sanna-Cherchi, S.; Bomback, A. S.; Canetta, P. A.; Appel, G. B.; Radhakrishnan, J.; Trimarchi, H.; Sprangers, B.; Cattran, D. C.; Reich, H.; Pei, Y.; Ravani, P.; Galesic, K.; Maixnerova, D.; Tesar, V.; Stengel, B.; Metzger, M.; Canaud, G.; Maillard, N.; Berthoux, F.; Berthelot, L.; Pillebout, E.; Monteiro, R.; Nelson, R.; Wyatt, R. J.; Smoyer, W.; Mahan, J.; Samhar, A. A.; Hidalgo, G.; Quiroga, A.; Weng, P.; Sreedharan, R.; Selewski, D.; Davis, K.; Kallash, M.; Vasylyeva, T. L.; Rheault, M.; Chishti, A.; Ranch, D.; Wenderfer, S. E.; Samsonov, D.; Claes, D. J.; Akchurin, O.; Goumenos, D.; Stangou, M.; Nagy, J.; Kovacs, T.; Fiaccadori, E.; Amoroso, A.; Barlassina, C.; Cusi, D.; Del Vecchio, L.; Battaglia, G. G.; Bodria, M.; Boer, E.; Bono, L.; Boscutti, G.; Caridi, G.; Lugani, F.; Ghiggeri, G. M.; Coppo, R.; Peruzzi, L.; Esposito, V.; Esposito, C.; Feriozzi, S.; Polci, R.; Frasca, G.; Galliani, M.; Garozzo, M.; Mitrotti, A.; Gesualdo, L.; Granata, S.; Zaza, G.; Londrino, F.; Magistroni, R.; Pisani, I.; Magnano, A.; Marcantoni, C.; Messa, P.; Mignani, R.; Pani, A.; Ponticelli, C.; Roccatello, D.; Salvadori, M.; Salvi, E.; Santoro, D.; Gembillo, G.; Savoldi, S.; Spotti, D.; Zamboli, P.; Izzi, C.. - In: NATURE GENETICS. - ISSN 1061-4036. - 55:7(2023), pp. 1091-1105. [10.1038/s41588-023-01422-x]
Kiryluk, K.; Sanchez-Rodriguez, E.; Zhou, X. J.; Zanoni, F.; Liu, L.; Mladkova, N.; Khan, A.; Marasa, M.; Zhang, J. Y.; Balderes, O.; Sanna-Cherchi, S.; Bomback, A. S.; Canetta, P. A.; Appel, G. B.; Radhakrishnan, J.; Trimarchi, H.; Sprangers, B.; Cattran, D. C.; Reich, H.; Pei, Y.; Ravani, P.; Galesic, K.; Maixnerova, D.; Tesar, V.; Stengel, B.; Metzger, M.; Canaud, G.; Maillard, N.; Berthoux, F.; Berthelot, L.; Pillebout, E.; Monteiro, R.; Nelson, R.; Wyatt, R. J.; Smoyer, W.; Mahan, J.; Samhar, A. A.; Hidalgo, G.; Quiroga, A.; Weng, P.; Sreedharan, R.; Selewski, D.; Davis, K.; Kallash, M.; Vasylyeva, T. L.; Rheault, M.; Chishti, A.; Ranch, D.; Wenderfer, S. E.; Samsonov, D.; Claes, D. J.; Akchurin, O.; Goumenos, D.; Stangou, M.; Nagy, J.; Kovacs, T.; Fiaccadori, E.; Amoroso, A.; Barlassina, C.; Cusi, D.; Del Vecchio, L.; Battaglia, G. G.; Bodria, M.; Boer, E.; Bono, L.; Boscutti, G.; Caridi, G.; Lugani, F.; Ghiggeri, G. M.; Coppo, R.; Peruzzi, L.; Esposito, V.; Esposito, C.; Feriozzi, S.; Polci, R.; Frasca, G.; Galliani, M.; Garozzo, M.; Mitrotti, A.; Gesualdo, L.; Granata, S.; Zaza, G.; Londrino, F.; Magistroni, R.; Pisani, I.; Magnano, A.; Marcantoni, C.; Messa, P.; Mignani, R.; Pani, A.; Ponticelli, C.; Roccatello, D.; Salvadori, M.; Salvi, E.; Santoro, D.; Gembillo, G.; Savoldi, S.; Spotti, D.; Zamboli, P.; Izzi, C.
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