Multi-population genome-wide association study implicates both immune and non-immune factors in the etiology of pediatric steroid sensitive nephrotic syndrome
Fiaccadori Enrico 1Morello William 2Tasic Velibor 3Santoro Domenica 4van Wijk Joanna A.E. 5Milo?evi? Danko 6Kiryluk Krzysztof 7Kenny Eimear E. 8Ghiggeri Gian Marco 9Vachvanichsanong Prayong 10Nozu Kandai 11Gharavi Ali 7Lin Fangmin 12Schreuder Michiel F. 13Ariceta Gema 14Jankauskiene Augustina 15Hildebrandt Friedhelm 16Song Kyuyoung 17Gupta Yask 7Nagano China 18Horinouchi Tomoko 11Mitrotti Adele 19Jin Gina 7Lim Tze Y 7Marasa Maddalena 7Turudic Daniel 6Pisani Isabella 1Saraga Marijan 20Bagga Arvind 21Teeninga Nynke 13Pollak Martin R. 22Kawai Yosuke 23Bodria Monica 24Hogan Julien 25Shril Shirlee 26Loos Ruth J.F. 27Sampson Matthew G. 28Magistroni Riccardo 29Zurowska Aleksandra 30Sanna-Cherchi Simone 7Jia Xiaoyuan 23Ahram Dina F. 7McNulty Michelle T. 31Montini Giovanni 32Jung Seulgi 17Zanoni Francesca 33Caridi Gianluca 34Cheong Hae Il 35Barry Alexandra 31Reiterova Jana 36Westland Rik 5Gesualdo Loreto 37Dossier Claire 25Sinha Aditi 21Tokunaga Katsushi 23Prikhodina Larisa 38Ronco Pierre 39Luo Yang 40Raychaudhuri Soumya 41Drozynska-Duklas Magdalena 30Maringhini Silvio 42Debiec Hanna 43Giordano Mario 44Scolari Francesco 45Iijima Kazumoto 46Colucci Manuela 47Weng Patricia L. 48Vivarelli Marina 49Sim?s e Silva Ana Cristina50
作者信息
- 1. Unit¨¤ Operativa Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Medicina e Chirurgia, Universit¨¤ di Parma
- 2. Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca?ˉ Granda-Ospedale Maggiore Policlinico
- 3. Department of Pediatric Nephrology, University Children?ˉs Hospital
- 4. Division of Nephrology and Dialysis Unit, University of Messina
- 5. Department of Pediatric Nephrology, VU University Medical Center
- 6. Department of Pediatric Nephrology, Dialysis and Transplantation, Clinical Hospital Hospital Center Zagreb, University of Zagreb Medical School
- 7. Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons
- 8. Institute for Genomic Health, Icahn School of Medicine at Mount Sinai||Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai||Division of General Internal Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai
- 9. Department of Nephrology and Renal Transplantation, IRCCS Instituto Giannina Gaslini||Department of Integrated Pediatric and Hemato-Oncology Sciences, Giannina Gaslini Institute||Laboratory on the Pathophysiology of Uremia, Giannina Gaslini Institute
- 10. Department of Pediatrics, Faculty of Medicine, Prince of Songkla University
- 11. Department of Pediatrics, Kobe University Graduate School of Medicine
- 12. Department of Pediatric, Division of Pediatric Nephrology, Columbia University Irving Medical Center New York-Presbyterian Morgan Stanley Children?ˉs Hospital in New York
- 13. Department of Pediatric Nephrology, Amalia Children?ˉs Hospital, Radboud University Medical Center
- 14. Pediatric Nephrology, Hospital Universitari Vall d?ˉHebron, Universitat Aut¨?noma de Barcelona
- 15. Institute of Clinical Medicine, Faculty of Medicine, Vilnius University
- 16. Division of Nephrology, Boston Children?ˉs Hospital||Department of Pediatrics, Harvard Medical School
- 17. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine
- 18. Division of Nephrology, Boston Children?ˉs Hospital||Kidney Disease Initiative, Broad Institute of MIT and Harvard||Department of Pediatrics, Kobe University Graduate School of Medicine
- 19. Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons||Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro
- 20. Department of Pediatrics, University of Split
- 21. Department of Pediatrics, AIIMS
- 22. Division of Nephrology, Beth Israel Deaconess Medical Center||Department of Pediatric, Division of Pediatric Nephrology, Columbia University Irving Medical Center New York-Presbyterian Morgan Stanley Children?ˉs Hospital in New York
- 23. Genome Medical Science Project (Toyama), National Center for Global Health and Medicine (NCGM)||Department of Human Genetics, Graduate School of Medicine, The University of Tokyo
- 24. Department of Nephrology and Renal Transplantation, IRCCS Instituto Giannina Gaslini
- 25. AP-HP, Pediatric Nephrology Department, H?pital Robert-Debr¨|
- 26. Department of Medicine, Boston Children?ˉs Hospital||Department of Pediatrics, Harvard Medical School
- 27. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- 28. Division of Nephrology, Boston Children?ˉs Hospital||Kidney Disease Initiative, Broad Institute of MIT and Harvard||Department of Pediatrics, Harvard Medical School
- 29. Department of Nephrology, Dialysis and Transplant Unit, University Hospital of Modena||Surgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University of Modena and Reggio Emilia
- 30. Department of Pediatrics, Nephrology and Hypertension, Medical University Gdansk
- 31. Division of Nephrology, Boston Children?ˉs Hospital||Kidney Disease Initiative, Broad Institute of MIT and Harvard
- 32. Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca?ˉ Granda-Ospedale Maggiore Policlinico||Department of Clinical Sciences and Community Health, University of Milan
- 33. Sorbonne Universit¨|, UPMC Paris 06, Institut National de la Sant¨| et de la Recherde M¨|dicale||Division of Transplantation, Department of Surgery, University of Pennsylvania
- 34. Laboratory on Molecular Nephrology, IRCCS Instituto Giannina Gaslini
- 35. Department of Pediatrics, Hallym University Sacred Heart Hospital
- 36. Department of Nephrology, Medicine and General University Hospital, Charles University
- 37. Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro
- 38. Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University
- 39. Sorbonne Universit¨|, UPMC Paris 06, Institut National de la Sant¨| et de la Recherde M¨|dicale||Department of Nephrology, Centre Hospitalier du Mans
- 40. Kennedy Institute of Rheumatology, University of Oxford||Center for Data Sciences, Brigham and Women?ˉs Hospital, Harvard Medical School||Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- 41. Center for Data Sciences, Brigham and Women?ˉs Hospital, Harvard Medical School||Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of MIT and Harvard||Department of Biomedical Informatics, Harvard Medical School||Centre for Genetics and Genomics Versus Arthritis, University of Manchester
- 42. Department of Pediatrics, ISMETT
- 43. Sorbonne Universit¨|, UPMC Paris 06, Institut National de la Sant¨| et de la Recherde M¨|dicale
- 44. Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro
- 45. Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Division of Nephrology and Dialysis, University of Brescia and ASST Spedali Civili of Brescia
- 46. Hyogo Prefectural Kobe Children?ˉs Hospital||Department of Advanced Pediatric Medicine, Kobe University Graduate School of Medicine
- 47. Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Ges¨′
- 48. Department of Pediatric Nephrology, UCLA Medical Center and UCLA Medical Center-Santa Monica
- 49. Division of Nephrology, and Dialysis, Department of Pediatric Subspecialities, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Ges¨′
- 50. Department of Pediatrics, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais
- 折叠
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 signals. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. We conducted a multi-population GWAS meta-analysis in 38,463 participants (2,440 cases) and population specific GWAS, discovering twelve significant associations (eight novel). Fine-mapping implicated specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk signal. Non-HLA loci colocalized with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs was lacking, but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associated with earlier disease onset in two independent cohorts. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers.引用本文复制引用
Fiaccadori Enrico,Morello William,Tasic Velibor,Santoro Domenica,van Wijk Joanna A.E.,Milo?evi? Danko,Kiryluk Krzysztof,Kenny Eimear E.,Ghiggeri Gian Marco,Vachvanichsanong Prayong,Nozu Kandai,Gharavi Ali,Lin Fangmin,Schreuder Michiel F.,Ariceta Gema,Jankauskiene Augustina,Hildebrandt Friedhelm,Song Kyuyoung,Gupta Yask,Nagano China,Horinouchi Tomoko,Mitrotti Adele,Jin Gina,Lim Tze Y,Marasa Maddalena,Turudic Daniel,Pisani Isabella,Saraga Marijan,Bagga Arvind,Teeninga Nynke,Pollak Martin R.,Kawai Yosuke,Bodria Monica,Hogan Julien,Shril Shirlee,Loos Ruth J.F.,Sampson Matthew G.,Magistroni Riccardo,Zurowska Aleksandra,Sanna-Cherchi Simone,Jia Xiaoyuan,Ahram Dina F.,McNulty Michelle T.,Montini Giovanni,Jung Seulgi,Zanoni Francesca,Caridi Gianluca,Cheong Hae Il,Barry Alexandra,Reiterova Jana,Westland Rik,Gesualdo Loreto,Dossier Claire,Sinha Aditi,Tokunaga Katsushi,Prikhodina Larisa,Ronco Pierre,Luo Yang,Raychaudhuri Soumya,Drozynska-Duklas Magdalena,Maringhini Silvio,Debiec Hanna,Giordano Mario,Scolari Francesco,Iijima Kazumoto,Colucci Manuela,Weng Patricia L.,Vivarelli Marina,Sim?s e Silva Ana Cristina.Multi-population genome-wide association study implicates both immune and non-immune factors in the etiology of pediatric steroid sensitive nephrotic syndrome[EB/OL].(2025-03-28)[2026-05-01].https://www.medrxiv.org/content/10.1101/2022.09.13.22279644.学科分类
医学研究方法/基础医学/儿科学
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