Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1091-1105 |
| Number of pages | 15 |
| Journal | Nature Genetics |
| Volume | 55 |
| Issue number | 7 |
| Early online date | 2023 |
| DOIs | |
| Publication status | Published - Jul 2023 |
Keywords
- Animals
- Genome-Wide Association Study
- Glomerulonephritis, IGA/drug therapy
- Immunoglobulin A/genetics
- Mice
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In: Nature Genetics, Vol. 55, No. 7, 07.2023, p. 1091-1105.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
AU - Kiryluk, Krzysztof
AU - Sanchez-Rodriguez, Elena
AU - Zhou, Xu-Jie
AU - Zanoni, Francesca
AU - Liu, Lili
AU - Mladkova, Nikol
AU - Khan, Atlas
AU - Marasa, Maddalena
AU - Zhang, Jun Y.
AU - Balderes, Olivia
AU - Sanna-Cherchi, Simone
AU - Bomback, Andrew S.
AU - Canetta, Pietro A.
AU - Appel, Gerald B.
AU - Radhakrishnan, Jai
AU - Trimarchi, Hernan
AU - Sprangers, Ben
AU - Cattran, Daniel C.
AU - Reich, Heather
AU - Pei, York
AU - Ravani, Pietro
AU - Galesic, Kresimir
AU - Maixnerova, Dita
AU - Tesar, Vladimir
AU - Stengel, Benedicte
AU - Metzger, Marie
AU - Canaud, Guillaume
AU - Maillard, Nicolas
AU - Berthoux, Francois
AU - Berthelot, Laureline
AU - Pillebout, Evangeline
AU - Monteiro, Renato
AU - Nelson, Raoul
AU - Wyatt, Robert J.
AU - Smoyer, William
AU - Mahan, John
AU - Samhar, Al-Akash
AU - Hidalgo, Guillermo
AU - Quiroga, Alejandro
AU - Weng, Patricia
AU - Sreedharan, Raji
AU - Selewski, David
AU - Davis, Keefe
AU - Kallash, Mahmoud
AU - Vasylyeva, Tetyana L.
AU - Rheault, Michelle
AU - Chishti, Aftab
AU - Ranch, Daniel
AU - Wenderfer, Scott E.
AU - Samsonov, Dmitry
AU - Claes, Donna J.
AU - Akchurin, Oleh
AU - Goumenos, Dimitrios
AU - Stangou, Maria
AU - Nagy, Judit
AU - Kovacs, Tibor
AU - Fiaccadori, Enrico
AU - Amoroso, Antonio
AU - Barlassina, Cristina
AU - Cusi, Daniele
AU - del Vecchio, Lucia
AU - Battaglia, Giovanni Giorgio
AU - Bodria, Monica
AU - Boer, Emanuela
AU - Bono, Luisa
AU - Boscutti, Giuliano
AU - Caridi, Gianluca
AU - Lugani, Francesca
AU - Ghiggeri, GianMarco
AU - Coppo, Rosanna
AU - Peruzzi, Licia
AU - Esposito, Vittoria
AU - Esposito, Ciro
AU - Feriozzi, Sandro
AU - Polci, Rosaria
AU - Frasca, Giovanni
AU - Galliani, Marco
AU - Garozzo, Maurizio
AU - Mitrotti, Adele
AU - Gesualdo, Loreto
AU - Granata, Simona
AU - Zaza, Gianluigi
AU - Londrino, Francesco
AU - Magistroni, Riccardo
AU - Pisani, Isabella
AU - Magnano, Andrea
AU - Marcantoni, Carmelita
AU - Messa, Piergiorgio
AU - Mignani, Renzo
AU - Pani, Antonello
AU - Ponticelli, Claudio
AU - Roccatello, Dario
AU - Salvadori, Maurizio
AU - Salvi, Erica
AU - Santoro, Domenico
AU - Gembillo, Guido
AU - Savoldi, Silvana
AU - Spotti, Donatella
AU - Zamboli, Pasquale
AU - Izzi, Claudia
AU - Alberici, Federico
AU - Delbarba, Elisa
AU - Florczak, Michał
AU - Krata, Natalia
AU - Mucha, Krzysztof
AU - Pączek, Leszek
AU - Niemczyk, Stanisław
AU - Moszczuk, Barbara
AU - Pańczyk-Tomaszewska, Malgorzata
AU - Mizerska-Wasiak, Malgorzata
AU - Perkowska-Ptasińska, Agnieszka
AU - Bączkowska, Teresa
AU - Durlik, Magdalena
AU - Pawlaczyk, Krzysztof
AU - Sikora, Przemyslaw
AU - Zaniew, Marcin
AU - Kaminska, Dorota
AU - Krajewska, Magdalena
AU - Kuzmiuk-Glembin, Izabella
AU - Heleniak, Zbigniew
AU - Bullo-Piontecka, Barbara
AU - Liberek, Tomasz
AU - Dębska-Slizien, Alicja
AU - Hryszko, Tomasz
AU - Materna-Kiryluk, Anna
AU - Miklaszewska, Monika
AU - Szczepańska, Maria
AU - Dyga, Katarzyna
AU - Machura, Edyta
AU - Siniewicz-Luzeńczyk, Katarzyna
AU - Pawlak-Bratkowska, Monika
AU - Tkaczyk, Marcin
AU - Runowski, Dariusz
AU - Kwella, Norbert
AU - Drożdż, Dorota
AU - Habura, Ireneusz
AU - Kronenberg, Florian
AU - Prikhodina, Larisa
AU - van Heel, David
AU - Fontaine, Bertrand
AU - Cotsapas, Chris
AU - Wijmenga, Cisca
AU - Franke, Andre
AU - Annese, Vito
AU - Gregersen, Peter K.
AU - Parameswaran, Sreeja
AU - Weirauch, Matthew
AU - Kottyan, Leah
AU - Harley, John B.
AU - Suzuki, Hitoshi
AU - Narita, Ichiei
AU - Goto, Shin
AU - Lee, Hajeong
AU - Kim, Dong Ki
AU - Kim, Yon Su
AU - Park, Jin-Ho
AU - Cho, BeLong
AU - Choi, Murim
AU - van Wijk, Ans
AU - Huerta, Ana
AU - Ars, Elisabet
AU - Ballarin, Jose
AU - Lundberg, Sigrid
AU - Vogt, Bruno
AU - Mani, Laila-Yasmin
AU - Caliskan, Yasar
AU - Barratt, Jonathan
AU - Abeygunaratne, Thilini
AU - Kalra, Philip A.
AU - Gale, Daniel P.
AU - Panzer, Ulf
AU - Rauen, Thomas
AU - Floege, J. rgen
AU - Schlosser, Pascal
AU - Ekici, Arif B.
AU - Eckardt, Kai-Uwe
AU - Chen, Nan
AU - Xie, Jingyuan
AU - Lifton, Richard P.
AU - Loos, Ruth J. F.
AU - Kenny, Eimear E.
AU - Ionita-Laza, Iuliana
AU - Köttgen, Anna
AU - Julian, Bruce A.
AU - Novak, Jan
AU - Scolari, Francesco
AU - Zhang, Hong
AU - Gharavi, Ali G.
N1 - Funding Information: We are grateful to all study participants across multiple nephrology centers worldwide for their contributions to this manuscript. This work was supported by the following institutions, grants and funding agencies: Columbia University, Columbia Glomerular Center, IGA Nephropathy Foundation of America and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01-DK105124 (to K.K., J. Novak, B.A.J.), RC2-DK116690 (to K.K.) and R01-DK082753 (to A.G.G., J. Novak, K.K., F.S., B.A.J., R.J.W.). Additional support was provided by R01LM013061 (to K.K.), U01HG008680 (to K.K.), U01AI152960 (to K.K.), R01-DK078244 (to J. Novak, B.A.J.), R01-AI149431 (to J. Novak, B.A.J.), National Science Foundation of China (82022010 to X.-J.Z.; 82070733 to H.Z.), Beijing Natural Science Foundation (Z190023 to X.-J.Z.), Deutsche Forschungsgemeinschaft (DFG) Project-ID 192904750—CRC 992 Medical Epigenetics (to A. Köttgen, P. Schlosser), DFG Project-ID 431984000—CRC 1453 (to A. Köttgen) and EQUIP Program for Medical Scientists, Faculty of Medicine, University of Freiburg (to P. Schlosser). J.B.H., S.P., L.K. and M.W. were supported by R01HG010730, U01AI130830, R01NS099068, R01AI024717, R01AR073228, U01AI150748, R01AI148276, P01AI150585 and the US Department of Veterans Affairs Merit Award I01-BX001834 to J.B.H. D.P.G. was supported by the St Peter’s Trust for Kidney, Bladder and Prostate Research. The UK cohort data were generated as a result of a grant from Kidney Research UK and the Medical Research Council (to J. Barratt and D.P.G.). The German STOP-IgAN study was supported by the DFG (German Research Foundation)—CRU 5011—Project-ID 445703531 (to J.F., T.R.). The GCKD study was funded by grants from the German Ministry of Education and Research (BMBF, 01ER0804) and the KfH Foundation for Preventive Medicine. Unregistered grants to support the study were provided by Bayer, Fresenius Medical Care and Amgen. Genotyping was supported by Bayer Pharma AG. The recruitment of Polish cases with IgAN was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Poznań University of Medical Sciences, Poland. The recruitment of Czech patients with IgAN was supported by the research project of General University Hospital in Prague (RVO-VFN64165). The recruitment of the Russian cohort was supported by the Government Assignment of the Russian Ministry of Health, Assignment 200080056 of the Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University. The recruitment of the Swedish cohort was supported by the Nephrology and Rheumatology Departments at Karolinska University Hospital and Karolinska Institutet, Stockholm, and grants from the Swedish Society of Medicine. We thank the Immunopathology Working Group of the Italian Society of Nephrology (ISN) for inviting their member sites to contribute to this study. We are also grateful to the Pediatric Nephrology Research Consortium (PNRC) for hosting and cosponsoring the GIGA-kids study that recruited pediatric patients with IgAN across the PNRC sites. We are additionally grateful to C. Bowers for coordinating GIGA-kids and PMRC-based recruitment, J. Narus for coordinating recruitment at the University of Utah, E. Elenberg and S. Shah for helping enroll participants from Texas Children’s Hospital and A. Suwanichkul for sample shipping. The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. We are grateful to the International Multiple Sclerosis Genetics Consortium (IMSGC), the Inflammatory Bowel Disease Genetics Consortium (IBDGC), the International Myositis Consortium (IMC), the Feinstein Institute for Medical Research, the French Biological Ressource Center for MS Genetics (REFGENSEP), Genethon and INSERM for contributing Immunochip controls for the purpose of this study. We also thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the NHGRI with cofunding from the NIMHD, for providing population controls genotyped with MEGA chip for this study. Molecular graphics shown in Extended Data Fig. were generated using UCSF Chimera, developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. The funding sources were not involved in the study design, collection, analysis and interpretation of data, writing of the report or the decision to submit the paper for publication. Funding Information: B.A.J. and J. Novak are cofounders, co-owners of, and consultants for Reliant Glycosciences, LLC, and are co-inventors on US patent application 14/318,082 (assigned to UAB Research Foundation). A.G.G. has served on an advisory board for Novartis, Travere and Natera and receives research grant funding from the Renal Research Institute and Natera. K.K. has served on an advisory board for Goldfinch Bio and Gilead. The other authors report no competing interests. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
KW - Animals
KW - Genome-Wide Association Study
KW - Glomerulonephritis, IGA/drug therapy
KW - Immunoglobulin A/genetics
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85162272555&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41588-023-01422-x
DO - https://doi.org/10.1038/s41588-023-01422-x
M3 - Article
C2 - 37337107
SN - 1061-4036
VL - 55
SP - 1091
EP - 1105
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -