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

Research output: Contribution to journalJournal articleResearchpeer-review

  • 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
  • Eimear E. Kenny
  • Iuliana Ionita-Laza
  • Anna Köttgen
  • Bruce A. Julian
  • Jan Novak
  • Francesco Scolari
  • Hong Zhang
  • Ali G. Gharavi

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 languageEnglish
JournalNature Genetics
Volume55
Issue number7
Pages (from-to)1091-1105
Number of pages15
ISSN1061-4036
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

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