Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome

Alexandra Barry, Michelle T. McNulty, Xiaoyuan Jia, Yask Gupta, Hanna Debiec, Yang Luo, China Nagano, Tomoko Horinouchi, Seulgi Jung, Manuela Colucci, Dina F. Ahram, Adele Mitrotti, Aditi Sinha, Nynke Teeninga, Gina Jin, Shirlee Shril, Gianluca Caridi, Monica Bodria, Tze Y. Lim, Rik Westland, Francesca Zanoni, Maddalena Marasa, Daniel Turudic, Mario Giordano, Loreto Gesualdo, Riccardo Magistroni, Isabella Pisani, Enrico Fiaccadori, Jana Reiterova, Silvio Maringhini, William Morello, Giovanni Montini, Patricia L. Weng, Francesco Scolari, Marijan Saraga, Velibor Tasic, Domenica Santoro, Joanna A. E. Wijk, Danko Milošević, Yosuke Kawai, Krzysztof Kiryluk, Martin R. Pollak, Ali Gharavi, Fangmin Lin, Ana Cristina Simœs e Silva, Ruth J. F. Loos, Eimear E. Kenny, Michiel F. Schreuder, Aleksandra Zurowska, Claire Dossier, Gema Ariceta, Magdalena Drozynska-Duklas, Julien Hogan, Augustina Jankauskiene, Friedhelm Hildebrandt, Larisa Prikhodina, Kyuyoung Song, Arvind Bagga, Hae Cheong, Gian Marco Ghiggeri, Prayong Vachvanichsanong, Kandai Nozu, Dongwon Lee, Marina Vivarelli, Soumya Raychaudhuri, Katsushi Tokunaga, Simone Sanna-Cherchi, Pierre Ronco, Kazumoto Iijima and Matthew G. Sampson ()
Additional contact information
Alexandra Barry: Boston Children’s Hospital
Michelle T. McNulty: Boston Children’s Hospital
Xiaoyuan Jia: National Center for Global Health and Medicine (NCGM)
Yask Gupta: Columbia University College of Physicians and Surgeons
Hanna Debiec: Institut National de la Santé et de la Recherde Médicale, Unité Mixte de Rechereche
Yang Luo: University of Oxford, Roosevelt Drive, Headington
China Nagano: Boston Children’s Hospital
Tomoko Horinouchi: Kobe University Graduate School of Medicine
Seulgi Jung: University of Ulsan College of Medicine
Manuela Colucci: Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù
Dina F. Ahram: Columbia University College of Physicians and Surgeons
Adele Mitrotti: Columbia University College of Physicians and Surgeons
Aditi Sinha: AIIMS
Nynke Teeninga: Radboud University Medical Center
Gina Jin: Columbia University College of Physicians and Surgeons
Shirlee Shril: Boston Children’s Hospital
Gianluca Caridi: IRCCS Instituto Giannina Gaslini
Monica Bodria: IRCCS Instituto Giannina Gaslini
Tze Y. Lim: Columbia University College of Physicians and Surgeons
Rik Westland: VU University Medical Center
Francesca Zanoni: Columbia University College of Physicians and Surgeons
Maddalena Marasa: Columbia University College of Physicians and Surgeons
Daniel Turudic: University of Zagreb Medical School
Mario Giordano: Bari Polyclinic Giovanni XXIII Children’s Hospital
Loreto Gesualdo: University of Bari Aldo Moro
Riccardo Magistroni: University Hospital of Modena
Isabella Pisani: Università di Parma
Enrico Fiaccadori: Università di Parma
Jana Reiterova: Medicine and General University Hospital, Charles University
Silvio Maringhini: ISMETT
William Morello: Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico
Giovanni Montini: Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico
Patricia L. Weng: UCLA Medical Center and UCLA Medical Center-Santa Monica
Francesco Scolari: University of Brescia and ASST Spedali Civili of Brescia
Marijan Saraga: University of Split
Velibor Tasic: University Children’s Hospital
Domenica Santoro: University of Messina
Joanna A. E. Wijk: VU University Medical Center
Danko Milošević: University of Zagreb Medical School
Yosuke Kawai: National Center for Global Health and Medicine (NCGM)
Krzysztof Kiryluk: Columbia University College of Physicians and Surgeons
Martin R. Pollak: Beth Israel Deaconess Medical Center
Ali Gharavi: Columbia University College of Physicians and Surgeons
Fangmin Lin: Columbia University Irving Medical Center New York-Presbyterian Morgan Stanley Children’s Hospital in New York
Ana Cristina Simœs e Silva: Federal University of Minas Gerais
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Eimear E. Kenny: Icahn School of Medicine at Mount Sinai
Michiel F. Schreuder: Radboud University Medical Center
Aleksandra Zurowska: Medical University Gdansk
Claire Dossier: Hôpital Robert-Debré
Gema Ariceta: Hospital Universitari Vall d’Hebron, Universitat Autónoma de Barcelona
Magdalena Drozynska-Duklas: Medical University Gdansk
Julien Hogan: Hôpital Robert-Debré
Augustina Jankauskiene: Vilnius University
Friedhelm Hildebrandt: Boston Children’s Hospital
Larisa Prikhodina: Pirogov Russian National Research Medical University
Kyuyoung Song: University of Ulsan College of Medicine
Arvind Bagga: AIIMS
Hae Cheong: Hallym University Sacred Heart Hospital
Gian Marco Ghiggeri: IRCCS Instituto Giannina Gaslini
Prayong Vachvanichsanong: Prince of Songkla University
Kandai Nozu: Kobe University Graduate School of Medicine
Dongwon Lee: Boston Children’s Hospital
Marina Vivarelli: Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù
Soumya Raychaudhuri: Brigham and Women’s Hospital, Harvard Medical School
Katsushi Tokunaga: National Center for Global Health and Medicine (NCGM)
Simone Sanna-Cherchi: Columbia University College of Physicians and Surgeons
Pierre Ronco: Institut National de la Santé et de la Recherde Médicale, Unité Mixte de Rechereche
Kazumoto Iijima: Hyogo Prefectural Kobe Children’s Hospital
Matthew G. Sampson: Boston Children’s Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37985-w

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