GWAS defines pathogenic signaling pathways and prioritizes drug targets for IgA nephropathy
Authors: Kiryluk Krzysztof , Sanchez-Rodriguez Elena , Zhou Xu-jie , Zanoni Francesca , Liu Lili , Mladkova Nikol , Khan Atlas , Marasa Maddalena , Zhang Jun Y. , Balderes Olivia , Sanna-Cherchi Simone , Bomback Andrew S. , Canetta Pietro A. , Appel Gerald B. , Radhakrishnan Jai , Trimarchi Hernan , Sprangers Ben , Cattran Daniel C. , Reich Heather , Pei York , Ravani Pietro , Galesic Kresimir , Maixnerova Dita , Tesar Vladimir , Stengel Benedicte , Metzger Marie , Canaud Guillaume , Maillard Nicolas , Berthoux Francois , Berthelot Laureline , Pillebout Evangeline , Monteiro Renato , Nelson Raoul , Wyatt Robert , Smoyer William , Mahan John , Samhar Al-Akash , Hidalgo Guillermo , Quiroga Alejandro , Weng Patricia , Sreedharan Raji , Selewski David , Davis Keefe , Kallash Mahmoud , Vasylyeva Tetyana L. , Rheault Michelle , Chishti Aftab , Ranch Daniel , Wenderfer Scott E. , Samsonov Dmitry , Claes Donna J. , Oleh Akchurin , Goumenos Dimitrios , Stangou Maria , Nagy Judit , Kovacs Tibor , Fiaccadori Enrico , Amoroso Antonio , Barlassina Cristina , Cusi Daniele , Vecchio Lucia Del , Battaglia Giovanni Giorgio , Bodria Monica , Boer Emanuela , Bono Luisa , Boscutti Giuliano , Caridi Gianluca , Lugani Francesca , Ghiggeri GianMarco , Coppo Rosanna , Peruzzi Licia , Esposito Vittoria , Esposito Ciro , Feriozzi Sandro , Polci Rosaria , Frasca Giovanni , 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 , Roccatello Dario , Salvadori Maurizio , Salvi Erica , 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 Malgorzata , Mizerska-Wasiak Malgorzata , Perkowska-Ptasińska Agnieszka , Bączkowska Teresa , Durlik Magdalena , Pawlaczyk Krzysztof , Sikora Przemyslaw , Zaniew Marcin , Kaminska Dorota , Krajewska Magdalena , Kuzmiuk-Glembin Izabella , Heleniak Zbigniew , Bullo-Piontecka Barbara , Liberek Tomasz , Dębska-Slizien Alicja , 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 Larisa , van Heel David , Fontaine Bertrand , Cotsapas Chris , Wijmenga Cisca , Franke Andre , Annese Vito , Gregersen Peter K. , Parameswaran Sreeja , Weirauch Matthew , Kottyan Leah , Harley John B , Suzuki Hitoshi , Narita Ichiei , Goto Shin , Lee Hajeong , Kim Dong Ki , Kim Yon Su , Park Jin-Ho , Cho BeLong , Choi Murim , Van Wijk Ans , Huerta Ana , Ars Elisabet , Ballarin Jose , Lundberg Sigrid , Vogt Bruno , Mani Laila-Yasmin , Caliskan Yasar , Barratt Jonathan , Abeygunaratne Thilini , Kalra Philip A. , Gale Daniel P. , Panzer Ulf , Rauen Thomas , Floege Jürgen , Schlosser Pascal , Ekici Arif B. , Eckardt Kai-Uwe , Chen Nan , Xie Jingyuan , Lifton Richard P. , Loos Ruth J. F. , Kenny Eimear E. , Ionita-Laza Iuliana , Köttgen Anna , Julian Bruce , Novak Jan , Scolari Francesco , Zhang Hong , Gharavi Ali G. 
Published: November 2021

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.