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