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

Krzysztof Kiryluk; Elena Sanchez-Rodriguez; Xu Jie Zhou; Francesca Zanoni; Lili Liu; Nikol Mladkova; Atlas Khan; Maddalena Marasa; Jun Y. Zhang; Olivia Balderes; Simone Sanna-Cherchi; Andrew S. Bomback; Pietro A. Canetta; Gerald B. Appel; Jai Radhakrishnan; Hernan Trimarchi; Ben Sprangers; Daniel C. Cattran; Heather Reich; York Pei; Pietro Ravani; Kresimir Galesic; Dita Maixnerova; Vladimir Tesar; Benedicte Stengel; Marie Metzger; Guillaume Canaud; Nicolas Maillard; Francois Berthoux; Laureline Berthelot; Evangeline Pillebout; Renato Monteiro; Raoul Nelson; Robert J. Wyatt; William Smoyer; John Mahan; Al Akash Samhar; Guillermo Hidalgo; Alejandro Quiroga; Patricia Weng; Raji Sreedharan; David Selewski; Keefe Davis; Mahmoud Kallash; Tetyana L. Vasylyeva; Michelle Rheault; Aftab Chishti; Daniel Ranch; Scott E. Wenderfer; Dmitry Samsonov; Donna J. Claes; Oleh Akchurin; Dimitrios Goumenos; Maria Stangou; Judit Nagy; Tibor Kovacs; Enrico Fiaccadori; Antonio Amoroso; Cristina Barlassina; Daniele Cusi; Lucia Del Vecchio; Giovanni Giorgio Battaglia; Monica Bodria; Emanuela Boer; Luisa Bono; Giuliano Boscutti; Gianluca Caridi; Francesca Lugani; Gian Marco Ghiggeri; Rosanna Coppo; Licia Peruzzi; Vittoria Esposito; Ciro Esposito; Sandro Feriozzi; Rosaria Polci; Giovanni Frasca; Marco Galliani; Maurizio Garozzo; Adele Mitrotti; Loreto Gesualdo; Simona Granata; Gianluigi Zaza; Francesco Londrino; Riccardo Magistroni; Isabella Pisani; Andrea Magnano; Carmelita Marcantoni; Piergiorgio Messa; Renzo Mignani; Antonello Pani; Claudio Ponticelli; Dario Roccatello; Maurizio Salvadori; Erica Salvi; Domenico Santoro; Guido Gembillo; Silvana Savoldi; Donatella Spotti; Pasquale Zamboli; Claudia Izzi; Federico Alberici; Elisa Delbarba; Michał Florczak; Natalia Krata; Krzysztof Mucha; Leszek Pączek; Stanisław Niemczyk; Barbara Moszczuk; Malgorzata Pańczyk-Tomaszewska; Malgorzata Mizerska-Wasiak; Agnieszka Perkowska-Ptasińska; Teresa Bączkowska; Magdalena Durlik; Krzysztof Pawlaczyk; Przemyslaw Sikora; Marcin Zaniew; Dorota Kaminska; Magdalena Krajewska; Izabella Kuzmiuk-Glembin; Zbigniew Heleniak; Barbara Bullo-Piontecka; Tomasz Liberek; Alicja Dębska-Slizien; Tomasz Hryszko; Anna Materna-Kiryluk; Monika Miklaszewska; Maria Szczepańska; Katarzyna Dyga; Edyta Machura; Katarzyna Siniewicz-Luzeńczyk; Monika Pawlak-Bratkowska; Marcin Tkaczyk; Dariusz Runowski; Norbert Kwella; Dorota Drożdż; Ireneusz Habura; Florian Kronenberg; Larisa Prikhodina; David van Heel; Bertrand Fontaine; Chris Cotsapas; Cisca Wijmenga; Andre Franke; Vito Annese; Peter K. Gregersen; Sreeja Parameswaran; Matthew Weirauch; Leah Kottyan; John B. Harley; Hitoshi Suzuki; Ichiei Narita; Shin Goto; Hajeong Lee; Dong Ki Kim; Yon Su Kim; Jin Ho Park; Be Long Cho; Murim Choi; Ans Van Wijk; Ana Huerta; Elisabet Ars; Jose Ballarin; Sigrid Lundberg; Bruno Vogt; Laila Yasmin Mani; Yasar Caliskan; Jonathan Barratt; Thilini Abeygunaratne; Philip A. Kalra; Daniel P. Gale; Ulf Panzer; Thomas Rauen; Jürgen Floege; Pascal Schlosser; Arif B. Ekici; Kai Uwe Eckardt; Nan Chen; Jingyuan Xie; Richard P. Lifton; Ruth J.F. Loos; Eimear E. Kenny; Iuliana Ionita-Laza; Anna Köttgen; Bruce A. Julian; Jan Novak; Francesco Scolari; Hong Zhang; Ali G. Gharavi

doi:10.1038/s41588-023-01422-x

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

Krzysztof Kiryluk, Elena Sanchez-Rodriguez, Xu Jie Zhou, Francesca Zanoni, Lili Liu, Nikol Mladkova, Atlas Khan, Maddalena Marasa, Jun Y. Zhang, Olivia Balderes, Simone Sanna-Cherchi, Andrew S. Bomback, Pietro A. Canetta, Gerald B. Appel, Jai Radhakrishnan, Hernan Trimarchi, Ben Sprangers, Daniel C. Cattran, Heather Reich, York PeiPietro Ravani, Kresimir Galesic, Dita Maixnerova, Vladimir Tesar, Benedicte Stengel, Marie Metzger, Guillaume Canaud, Nicolas Maillard, Francois Berthoux, Laureline Berthelot, Evangeline Pillebout, Renato Monteiro, Raoul Nelson, Robert J. Wyatt, William Smoyer, John Mahan, Al Akash Samhar, Guillermo Hidalgo, Alejandro Quiroga, Patricia Weng, Raji Sreedharan, David Selewski, Keefe Davis, Mahmoud Kallash, Tetyana L. Vasylyeva, Michelle Rheault, Aftab Chishti, Daniel Ranch, Scott E. Wenderfer, Dmitry Samsonov, Donna J. Claes, Oleh Akchurin, Dimitrios Goumenos, Maria Stangou, Judit Nagy, Tibor Kovacs, Enrico Fiaccadori, Antonio Amoroso, Cristina Barlassina, Daniele Cusi, Lucia Del Vecchio, Giovanni Giorgio Battaglia, Monica Bodria, Emanuela Boer, Luisa Bono, Giuliano Boscutti, Gianluca Caridi, Francesca Lugani, Gian Marco Ghiggeri, Rosanna Coppo, Licia Peruzzi, Vittoria Esposito, Ciro Esposito, Sandro Feriozzi, Rosaria Polci, Giovanni Frasca, Marco Galliani, Maurizio Garozzo, Adele Mitrotti, Loreto Gesualdo, Simona Granata, Gianluigi Zaza, Francesco Londrino, Riccardo Magistroni, Isabella Pisani, Andrea Magnano, Carmelita Marcantoni, Piergiorgio Messa, Renzo Mignani, Antonello Pani, Claudio Ponticelli, Dario Roccatello, Maurizio Salvadori, Erica Salvi, Domenico Santoro, Guido Gembillo, Silvana Savoldi, Donatella Spotti, Pasquale Zamboli, Claudia Izzi, Federico Alberici, Elisa Delbarba, Michał Florczak, Natalia Krata, Krzysztof Mucha, Leszek Pączek, Stanisław Niemczyk, Barbara Moszczuk, Malgorzata Pańczyk-Tomaszewska, Malgorzata Mizerska-Wasiak, Agnieszka Perkowska-Ptasińska, Teresa Bączkowska, Magdalena Durlik, Krzysztof Pawlaczyk, Przemyslaw Sikora, Marcin Zaniew, Dorota Kaminska, Magdalena Krajewska, Izabella Kuzmiuk-Glembin, Zbigniew Heleniak, Barbara Bullo-Piontecka, Tomasz Liberek, Alicja Dębska-Slizien, Tomasz Hryszko, Anna Materna-Kiryluk, Monika Miklaszewska, Maria Szczepańska, Katarzyna Dyga, Edyta Machura, Katarzyna Siniewicz-Luzeńczyk, Monika Pawlak-Bratkowska, Marcin Tkaczyk, Dariusz Runowski, Norbert Kwella, Dorota Drożdż, Ireneusz Habura, Florian Kronenberg, Larisa Prikhodina, David van Heel, Bertrand Fontaine, Chris Cotsapas, Cisca Wijmenga, Andre Franke, Vito Annese, Peter K. Gregersen, Sreeja Parameswaran, Matthew Weirauch, Leah Kottyan, John B. Harley, Hitoshi Suzuki, Ichiei Narita, Shin Goto, Hajeong Lee, Dong Ki Kim, Yon Su Kim, Jin Ho Park, Be Long Cho, Murim Choi, Ans Van Wijk, Ana Huerta, Elisabet Ars, Jose Ballarin, Sigrid Lundberg, Bruno Vogt, Laila Yasmin Mani, Yasar Caliskan, Jonathan Barratt, Thilini Abeygunaratne, Philip A. Kalra, Daniel P. Gale, Ulf Panzer, Thomas Rauen, Jürgen Floege, Pascal Schlosser, Arif B. Ekici, Kai Uwe Eckardt, Nan Chen, Jingyuan Xie, Richard P. Lifton, Ruth J.F. Loos, Eimear E. Kenny, Iuliana Ionita-Laza, Anna Köttgen, Bruce A. Julian, Jan Novak, Francesco Scolari, Hong Zhang, Ali G. Gharavi

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1091-1105
Number of pages	15
Journal	Nature Genetics
Volume	55
Issue number	7
DOIs	https://doi.org/10.1038/s41588-023-01422-x
State	Published - Jul 2023
Externally published	Yes

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/s41588-023-01422-x

Cite this

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., ... Gharavi, A. G. (2023). Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nature Genetics, 55(7), 1091-1105. https://doi.org/10.1038/s41588-023-01422-x

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, RJF, Kenny, EE, Ionita-Laza, I, Köttgen, A, Julian, BA, Novak, J, Scolari, F, Zhang, H & Gharavi, AG 2023, 'Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy', Nature Genetics, vol. 55, no. 7, pp. 1091-1105. https://doi.org/10.1038/s41588-023-01422-x

@article{ccbe7a347fb040b0a7caaef924cd491c,

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

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.",

author = "Krzysztof Kiryluk and Elena Sanchez-Rodriguez and Zhou, {Xu Jie} and Francesca Zanoni and Lili Liu and Nikol Mladkova and Atlas Khan and Maddalena Marasa and Zhang, {Jun Y.} and Olivia Balderes and Simone Sanna-Cherchi and Bomback, {Andrew S.} and Canetta, {Pietro A.} and Appel, {Gerald B.} and Jai Radhakrishnan and Hernan Trimarchi and Ben Sprangers and Cattran, {Daniel C.} and Heather Reich and York Pei and Pietro Ravani and Kresimir Galesic and Dita Maixnerova and Vladimir Tesar and Benedicte Stengel and Marie Metzger and Guillaume Canaud and Nicolas Maillard and Francois Berthoux and Laureline Berthelot and Evangeline Pillebout and Renato Monteiro and Raoul Nelson and Wyatt, {Robert J.} and William Smoyer and John Mahan and Samhar, {Al Akash} and Guillermo Hidalgo and Alejandro Quiroga and Patricia Weng and Raji Sreedharan and David Selewski and Keefe Davis and Mahmoud Kallash and Vasylyeva, {Tetyana L.} and Michelle Rheault and Aftab Chishti and Daniel Ranch and Wenderfer, {Scott E.} and Dmitry Samsonov and Claes, {Donna J.} and Oleh Akchurin and Dimitrios Goumenos and Maria Stangou and Judit Nagy and Tibor Kovacs and Enrico Fiaccadori and Antonio Amoroso and Cristina Barlassina and Daniele Cusi and {Del Vecchio}, Lucia and Battaglia, {Giovanni Giorgio} and Monica Bodria and Emanuela Boer and Luisa Bono and Giuliano Boscutti and Gianluca Caridi and Francesca Lugani and Ghiggeri, {Gian Marco} and Rosanna Coppo and Licia Peruzzi and Vittoria Esposito and Ciro Esposito and Sandro Feriozzi and Rosaria Polci and Giovanni Frasca and Marco Galliani and Maurizio Garozzo and Adele Mitrotti and Loreto Gesualdo and Simona Granata and Gianluigi Zaza and Francesco Londrino and Riccardo Magistroni and Isabella Pisani and Andrea Magnano and Carmelita Marcantoni and Piergiorgio Messa and Renzo Mignani and Antonello Pani and Claudio Ponticelli and Dario Roccatello and Maurizio Salvadori and Erica Salvi and Domenico Santoro and Guido Gembillo and Silvana Savoldi and Donatella Spotti and Pasquale Zamboli and Claudia Izzi and Federico Alberici and Elisa Delbarba and Micha{\l} Florczak and Natalia Krata and Krzysztof Mucha and Leszek P{\c a}czek and Stanis{\l}aw Niemczyk and Barbara Moszczuk and Malgorzata Pa{\'n}czyk-Tomaszewska and Malgorzata Mizerska-Wasiak and Agnieszka Perkowska-Ptasi{\'n}ska and Teresa B{\c a}czkowska and Magdalena Durlik and Krzysztof Pawlaczyk and Przemyslaw Sikora and Marcin Zaniew and Dorota Kaminska and Magdalena Krajewska and Izabella Kuzmiuk-Glembin and Zbigniew Heleniak and Barbara Bullo-Piontecka and Tomasz Liberek and Alicja D{\c e}bska-Slizien and Tomasz Hryszko and Anna Materna-Kiryluk and Monika Miklaszewska and Maria Szczepa{\'n}ska and Katarzyna Dyga and Edyta Machura and Katarzyna Siniewicz-Luze{\'n}czyk and Monika Pawlak-Bratkowska and Marcin Tkaczyk and Dariusz Runowski and Norbert Kwella and Dorota Dro{\.z}d{\.z} and Ireneusz Habura and Florian Kronenberg and Larisa Prikhodina and {van Heel}, David and Bertrand Fontaine and Chris Cotsapas and Cisca Wijmenga and Andre Franke and Vito Annese and Gregersen, {Peter K.} and Sreeja Parameswaran and Matthew Weirauch and Leah Kottyan and Harley, {John B.} and Hitoshi Suzuki and Ichiei Narita and Shin Goto and Hajeong Lee and Kim, {Dong Ki} and Kim, {Yon Su} and Park, {Jin Ho} and Cho, {Be Long} and Murim Choi and {Van Wijk}, Ans and Ana Huerta and Elisabet Ars and Jose Ballarin and Sigrid Lundberg and Bruno Vogt and Mani, {Laila Yasmin} and Yasar Caliskan and Jonathan Barratt and Thilini Abeygunaratne and Kalra, {Philip A.} and Gale, {Daniel P.} and Ulf Panzer and Thomas Rauen and J{\"u}rgen Floege and Pascal Schlosser and Ekici, {Arif B.} and Eckardt, {Kai Uwe} and Nan Chen and Jingyuan Xie and Lifton, {Richard P.} and Loos, {Ruth J.F.} and Kenny, {Eimear E.} and Iuliana Ionita-Laza and Anna K{\"o}ttgen and Julian, {Bruce A.} and Jan Novak and Francesco Scolari and Hong Zhang and Gharavi, {Ali G.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = jul,

doi = "10.1038/s41588-023-01422-x",

language = "English (US)",

volume = "55",

pages = "1091--1105",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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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, Gian Marco

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, Be Long

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, Jürgen

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85162272555&partnerID=8YFLogxK

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U2 - 10.1038/s41588-023-01422-x

DO - 10.1038/s41588-023-01422-x

M3 - Article

C2 - 37337107

AN - SCOPUS:85162272555

SN - 1061-4036

VL - 55

SP - 1091

EP - 1105

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

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