Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome
Barry, Alexandra (Broad Institute of MIT and Harvard)
McNulty, Michelle T. (Broad Institute of MIT and Harvard)
Jia, Xiaoyuan (The University of Tokyo)
Gupta, Yask (Columbia University College of Physicians and Surgeons)
Debiec, Hanna (Institut National de la Santé et de la Recherde Médicale)
Luo, Yang (Broad Institute of MIT and Harvard)
Nagano, China (Kobe University Graduate School of Medicine)
Horinouchi, Tomoko (Kobe University Graduate School of Medicine)
Jung, Seulgi (University of Ulsan College of Medicine)
Colucci, Manuela (Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù)
Ahram, Dina F. (Columbia University College of Physicians and Surgeons)
Mitrotti, Adele (University of Bari Aldo Moro)
Sinha, Aditi (AIIMS)
Teeninga, Nynke (Radboud University Medical Center)
Jin, Gina (Columbia University College of Physicians and Surgeons)
Shril, Shirlee (Harvard Medical School)
Caridi, Gianluca (IRCCS Instituto Giannina Gaslini)
Bodria, Monica (IRCCS Instituto Giannina Gaslini)
Lim, Tze Y. (Columbia University College of Physicians and Surgeons)
Westland, Rik (Amsterdam UMC. University Medical Center)
Zanoni, Francesca (University of Pennsylvania)
Marasa, Maddalena (Columbia University College of Physicians and Surgeons)
Turudic, Daniel (University of Zagreb Medical School)
Giordano, Mario (Bari Polyclinic Giovanni XXIII Children's Hospital)
Gesualdo, Loreto (University of Bari Aldo Moro)
Magistroni, Riccardo (University of Modena and Reggio Emilia)
Pisani, Isabella (Università di Parma)
Fiaccadori, Enrico (Università di Parma)
Reiterova, Jana (Charles University)
Maringhini, Silvio (ISMETT)
Morello, William (Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico)
Montini, Giovanni (University of Milan)
Weng, Patricia L. (UCLA Medical Center and UCLA Medical Center-Santa Monica)
Scolari, Francesco (University of Brescia and ASST Spedali Civili of Brescia)
Saraga, Marijan (University of Split)
Tasic, Velibor (University Children's Hospital Macedonia)
Santoro, Domenica (University of Messina)
van Wijk, Joanna A. E. (Amsterdam UMC. University Medical Center)
Milošević, Danko (Croatian Academy of Medical Sciences)
Kawai, Yosuke (The University of Tokyo)
Kiryluk, Krzysztof (Columbia University College of Physicians and Surgeons)
Pollak, Martin R. (Columbia University Irving Medical Center New York-Presbyterian Morgan Stanley Children's Hospital in New York)
Gharavi, Ali (Columbia University College of Physicians and Surgeons)
Lin, Fangmin (Columbia University Irving Medical Center New York-Presbyterian Morgan Stanley Children's Hospital in New York)
Simœs e Silva, Ana Cristina (Federal University of Minas Gerais)
Loos, Ruth J. F. (Icahn School of Medicine at Mount Sinai)
Kenny, Eimear E. (Icahn School of Medicine at Mount Sinai)
Schreuder, Michiel F. (Radboud University Medical Center)
Zurowska, Aleksandra (Medical University Gdansk.)
Dossier, Claire (Hôpital Robert-Debré)
Ariceta Iraola, Gema (Hospital Universitari Vall d'Hebron)
Drozynska-Duklas, Magdalena (Medical University Gdansk)
Hogan, Julien (Hôpital Robert-Debré)
Jankauskiene, Augustina (Vilnius University)
Hildebrandt, Friedhelm (Harvard Medical School)
Prikhodina, Larisa (Pirogov Russian National Research Medical University)
Song, Kyuyoung (University of Ulsan College of Medicine)
Bagga, Arvind (AIIMS)
Cheong, Hae (Hallym University Sacred Heart Hospital)
Ghiggeri, Gian Marco (IRCCS Instituto Giannina Gaslini)
Vachvanichsanong, Prayong (Prince of Songkla University)
Nozu, Kandai (Kobe University Graduate School of Medicine)
Lee, Dongwon (Harvard Medical School)
Vivarelli, Marina (Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù)
Raychaudhuri, Soumya (University of Manchester)
Tokunaga, Katsushi (The University of Tokyo)
Sanna-Cherchi, Simone (Columbia University College of Physicians and Surgeons)
Ronco, Pierre (Centre Hospitalier du Mans)
Iijima, Kazumoto (Kobe University Graduate School of Medicine)
Sampson, Matthew G. (Brigham and Women's Hospital (Boston, Estats Units d'Amèrica))
Universitat Autònoma de Barcelona

Date:	2023
Abstract:	Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations. Here, the authors have performed a multi-population GWAS meta-analysis of pediatric steroid sensitive nephrotic syndrome cases to discover 12 loci (4 novel), fine-map HLA, implicate kidney and immune factors, and associate the polygenic risk score with earlier disease onset.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Minimal change disease ; Genetics ; Paediatric kidney disease
Published in:	Nature communications, Vol. 14 (april 2023) , ISSN 2041-1723

DOI: 10.1038/s41467-023-37985-w
PMID: 37120605

13 p, 1.9 MB

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