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.;Alberici F.;Delbarba E.;Florczak M.;Krata N.;Mucha K.;Paczek L.;Niemczyk S.;Moszczuk B.;Panczyk-Tomaszewska M.;Mizerska-Wasiak M.;Perkowska-Ptasinska A.;Baczkowska T.;Durlik M.;Pawlaczyk K.;Sikora P.;Zaniew M.;Kaminska D.;Krajewska M.;Kuzmiuk-Glembin I.;Heleniak Z.;Bullo-Piontecka B.;Liberek T.;Debska-Slizien A.;Hryszko T.;Materna-Kiryluk A.;Miklaszewska M.;Szczepanska M.;Dyga K.;Machura E.;Siniewicz-Luzenczyk K.;Pawlak-Bratkowska M.;Tkaczyk M.;Runowski D.;Kwella N.;Drozdz D.;Habura I.;Kronenberg F.;Prikhodina L.;van Heel D.;Fontaine B.;Cotsapas C.;Wijmenga C.;Franke A.;Annese V.;Gregersen P. K.;Parameswaran S.;Weirauch M.;Kottyan L.;Harley J. B.;Suzuki H.;Narita I.;Goto S.;Lee H.;Kim D. K.;Kim Y. S.;Park J. -H.;Cho B. L.;Choi M.;Van Wijk A.;Huerta A.;Ars E.;Ballarin J.;Lundberg S.;Vogt B.;Mani L. -Y.;Caliskan Y.;Barratt J.;Abeygunaratne T.;Kalra P. A.;Gale D. P.;Panzer U.;Rauen T.;Floege J.;Schlosser P.;Ekici A. B.;Eckardt K. -U.;Chen N.;Xie J.;Lifton R. P.;Loos R. J. F.;Kenny E. E.;Ionita-Laza I.;Kottgen A.;Julian B. A.;Novak J.;Scolari F.;Zhang H.;Gharavi A. G.

2023-01-01

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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.