Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Kiryluk K, Sanchez-Rodriguez E, Zhou XJ, Zanoni F, Liu L, Mladkova N, Khan A, Marasa M, Zhang JY, Balderes O, Sanna-Cherchi S, Bomback AS, Canetta PA, Appel GB, Radhakrishnan J, Trimarchi H, Sprangers B, Cattran DC, 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 RJ, Smoyer W, Mahan J, Samhar AA, Hidalgo G, Quiroga A, Weng P, Sreedharan R, Selewski D, Davis K, Kallash M, Vasylyeva TL, Rheault M, Chishti A, Ranch D, Wenderfer SE, Samsonov D, Claes DJ, Akchurin O, Goumenos D, Stangou M, Nagy J, Kovacs T, Fiaccadori E, Amoroso A, Barlassina C, Cusi D, Del Vecchio L, Battaglia GG, Bodria M, Boer E, Bono L, Boscutti G, Caridi G, Lugani F, Ghiggeri GM, 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, Pączek L, Niemczyk S, Moszczuk B, Pańczyk-Tomaszewska M, Mizerska-Wasiak M, Perkowska-Ptasińska A, Bączkowska T, Durlik M, Pawlaczyk K, Sikora P, Zaniew M, Kaminska D, Krajewska M, Kuzmiuk-Glembin I, Heleniak Z, Bullo-Piontecka B, Liberek T, Dębska-Slizien A, Hryszko T, Materna-Kiryluk A, Miklaszewska M, Szczepańska M, Dyga K, Machura E, Siniewicz-Luzeńczyk K, Pawlak-Bratkowska M, Tkaczyk M, Runowski D, Kwella N, Drożdż D, Habura I, Kronenberg F, Prikhodina L, van Heel D, Fontaine B, Cotsapas C, Wijmenga C, Franke A, Annese V, Gregersen PK, Parameswaran S, Weirauch M, Kottyan L, Harley JB, Suzuki H, Narita I, Goto S, Lee H, Kim DK, Kim YS, Park JH, Cho BL, Choi M, Van Wijk A, Huerta A, Ars E, Ballarin J, Lundberg S, Vogt B, Mani LY, Caliskan Y, Barratt J, Abeygunaratne T, Kalra PA, Gale DP, Panzer U, Rauen T, Floege J, Schlosser P, Ekici AB, Eckardt KU, Chen N, Xie J, Lifton RP, Loos RJ, Kenny EE, Ionita-Laza I, Köttgen A, Julian BA, Novak J, Scolari F, Zhang H, Gharavi AG (2023)


Publication Type: Journal article

Publication year: 2023

Journal

DOI: 10.1038/s41588-023-01422-x

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.

Authors with CRIS profile

Involved external institutions

University of Calgary CA Canada (CA) University of Zagreb / Sveučilište u Zagrebu HR Croatia (HR) General University Hospital in Prague / Všeobecná Fakultní Nemocnice v Praze (VFN) CZ Czech Republic (CZ) Research Center in Epidemiology and Population Health / Centre de recherche en Epidémiologie et Santé des Populations (CESP) FR France (FR) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) FR France (FR) Centre de Recherche sur l'Inflammation (CRI) FR France (FR) University of Utah US United States (USA) (US) The University of Tennessee Health Science Center US United States (USA) (US) Nationwide Children's Hospital US United States (USA) (US) Driscoll Children's Hospital US United States (USA) (US) Helen DeVos Children's Hospital US United States (USA) (US) Children's Hospital Los Angeles US United States (USA) (US) Medical College of Wisconsin (MCW) US United States (USA) (US) C. S. Mott Children's Hospital US United States (USA) (US) Medical University of South Carolina (MUSC) US United States (USA) (US) University of Kentucky US United States (USA) (US) Baylor College of Medicine US United States (USA) (US) Boston Children's Hospital US United States (USA) (US) Weill Cornell Medicine US United States (USA) (US) Aristotle University of Thessaloniki GR Greece (GR) University of Pécs / Pécsi Tudományegyetem HU Hungary (HU) University of Turin / Università degli Studi di Torino (UNITO) IT Italy (IT) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu PL Poland (PL) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu PL Poland (PL) Medical University of Lublin / Uniwersytet Medyczny w Lublinie PL Poland (PL) University of Zielona Góra / Uniwersytet Zielonogórski PL Poland (PL) Medical University Gdansk / Gdański Uniwersytet Medyczny PL Poland (PL) Medical University of Bialystok PL Poland (PL) Jagiellonian University Medical College PL Poland (PL) Medical University of Silesia in Katowice / Śląski Uniwersytet Medyczny w Katowicach (SUM) PL Poland (PL) Université Paris-Sud FR France (FR) University at Buffalo. State University of New York US United States (USA) (US) University of Minnesota (UMN) US United States (USA) (US) New York Medical College (NYMC) US United States (USA) (US) University of Parma / Università degli Studi di Parma IT Italy (IT) Istituto Giannina Gaslini IT Italy (IT) Università degli Studi di Pavia IT Italy (IT) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) IT Italy (IT) Charité - Universitätsmedizin Berlin DE Germany (DE) Columbia University US United States (USA) (US) Columbia University Irving Medical Center (CUIMC) US United States (USA) (US) Peking University First Hospital / 北大国际医院 CN China (CN) Hospital Británico de Buenos Aires / Buenos Aires British Hospital AR Argentina (AR) Rega Institute for Medical Research BE Belgium (BE) University of Toronto CA Canada (CA) Hackensack Meridian Health US United States (USA) (US) Università degli studi di Milano IT Italy (IT) Azienda Socio Sanitaria Territoriale Lariana IT Italy (IT) University of Messina / Università degli Studi di Messina IT Italy (IT) Ospedale di Gorizia IT Italy (IT) A.R.N.A.S. Ospedali Civico Di Cristina Benfratelli IT Italy (IT) Ospedale Infantile "Regina Margherita" IT Italy (IT) Ospedale di Belcolle IT Italy (IT) Sandro Pertini Hospital / Ospedale Sandro Pertini IT Italy (IT) University of Bari Aldo Moro / Università degli Studi di Bari Aldo Moro IT Italy (IT) University of Verona / Università degli Studi di Verona IT Italy (IT) Azienda ospedaliera Sant'Andrea IT Italy (IT) Università degli Studi di Modena e Reggio Emilia (UNIMORE) IT Italy (IT) Policlinico San Marco IT Italy (IT) Azienda Unità Sanitaria della Romagna, Biella, Italy IT Italy (IT) Brotzu Hospital IT Italy (IT) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico IT Italy (IT) Careggi University Hospital / Azienda Ospedaliero Universitaria Careggi IT Italy (IT) Azienda Sanitaria Locale TO4 (ASL TO4) IT Italy (IT) NephroCare IT Italy (IT) Università degli Studi di Brescia IT Italy (IT) Wojskowy Instytut Medyczny PL Poland (PL) Instytut Centrum Zdrowia Matki Polki w Łodzi (ICZMP) / Polish Mother’s Memorial Hospital Research Institute PL Poland (PL) Veterans Health Administration (VHA) US United States (USA) (US) Juntendo University JP Japan (JP) University Hospitals of Leicester NHS Trust GB United Kingdom (GB) Salford Royal Hospital GB United Kingdom (GB) University College London (UCL) GB United Kingdom (GB) Universität Hamburg (UHH) DE Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Universitätsklinikum Freiburg DE Germany (DE) Ruijin Hospital / 上海交通大学医学院附属瑞金医院 / St. Marie Hospital CN China (CN) Yale School of Medicine US United States (USA) (US) Icahn School of Medicine at Mount Sinai US United States (USA) (US) University of Alabama at Birmingham (UAB) US United States (USA) (US) Children's Memorial Health Institute / Instytut "Pomnik - Centrum Zdrowia Dziecka" PL Poland (PL) University of Warmia and Mazury in Olsztyn PL Poland (PL) Medizinische Universität Innsbruck AT Austria (AT) Pirogov Russian National Research Medical University (RSMU / RNRMU) RU Russian Federation (RU) Queen Mary, University of London GB United Kingdom (GB) Sorbonne Université FR France (FR) Yale University US United States (USA) (US) University of Groningen / Rijksuniversiteit Groningen NL Netherlands (NL) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Northwell Health US United States (USA) (US) Cincinnati Children's Hospital Medical Center US United States (USA) (US) Niigata University / 新潟大学 JP Japan (JP) Seoul National University (SNU) / 서울대학교 KR Korea, Republic of (KR) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra NL Netherlands (NL) Hospital Universitario Puerta de Hierro - Majadahonda ES Spain (ES) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona ES Spain (ES) Danderyds sjukhus SE Sweden (SE) Inselspital, Universitätsspital Bern CH Switzerland (CH) Saint Louis University (SLU) US United States (USA) (US)

How to cite

APA:

Kiryluk, K., Sanchez-Rodriguez, E., Zhou, X.J., Zanoni, F., Liu, L., Mladkova, N.,... Gharavi, A.G. (2023). Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nature Genetics. https://doi.org/10.1038/s41588-023-01422-x

MLA:

Kiryluk, Krzysztof, et al. "Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy." Nature Genetics (2023).

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