Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome
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Published:2023-04-29
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Barry Alexandra, McNulty Michelle T.ORCID, Jia Xiaoyuan, Gupta Yask, Debiec Hanna, Luo YangORCID, Nagano ChinaORCID, Horinouchi TomokoORCID, Jung SeulgiORCID, Colucci Manuela, Ahram Dina F., Mitrotti Adele, Sinha Aditi, Teeninga Nynke, Jin Gina, Shril Shirlee, Caridi GianlucaORCID, Bodria Monica, Lim Tze Y., Westland RikORCID, Zanoni Francesca, Marasa MaddalenaORCID, Turudic Daniel, Giordano Mario, Gesualdo Loreto, Magistroni RiccardoORCID, Pisani Isabella, Fiaccadori Enrico, Reiterova Jana, Maringhini Silvio, Morello WilliamORCID, Montini GiovanniORCID, Weng Patricia L., Scolari Francesco, Saraga Marijan, Tasic VeliborORCID, Santoro Domenica, van Wijk Joanna A. E., Milošević Danko, Kawai YosukeORCID, Kiryluk Krzysztof, Pollak Martin R., Gharavi AliORCID, Lin FangminORCID, Simœs e Silva Ana CristinaORCID, Loos Ruth J. F.ORCID, Kenny Eimear E., Schreuder Michiel F.ORCID, Zurowska Aleksandra, Dossier Claire, Ariceta GemaORCID, Drozynska-Duklas Magdalena, Hogan Julien, Jankauskiene Augustina, Hildebrandt FriedhelmORCID, Prikhodina LarisaORCID, Song KyuyoungORCID, Bagga Arvind, Cheong HaeORCID, Ghiggeri Gian MarcoORCID, Vachvanichsanong Prayong, Nozu KandaiORCID, Lee DongwonORCID, Vivarelli MarinaORCID, Raychaudhuri SoumyaORCID, Tokunaga KatsushiORCID, Sanna-Cherchi SimoneORCID, Ronco PierreORCID, Iijima Kazumoto, Sampson Matthew G.ORCID
Abstract
AbstractPediatric 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.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases A gift from The Pura Vida Kidney Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference90 articles.
1. Noone, D. G., Iijima, K. & Parekh, R. Idiopathic nephrotic syndrome in children. Lancet 392, 61–74 (2018). 2. Gipson, D. S. et al. Gaining the PROMIS perspective from children with nephrotic syndrome: a Midwest pediatric nephrology consortium study. Health Qual. Life Outcomes 11, 30 (2013). 3. Ruth, E. M., Landolt, M. A., Neuhaus, T. J. & Kemper, M. J. Health-related quality of life and psychosocial adjustment in steroid-sensitive nephrotic syndrome. J. Pediatr. 145, 778–783 (2004). 4. Kerlin, B. A. et al. Epidemiology and risk factors for thromboembolic complications of childhood nephrotic syndrome: a Midwest Pediatric Nephrology Consortium (MWPNC) study. J. Pediatr. 155, 105–110 (2009). 5. Hingorani, S. R., Weiss, N. S. & Watkins, S. L. Predictors of peritonitis in children with nephrotic syndrome. Pediatr. Nephrol. Berl. Ger. 17, 678–682 (2002).
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