Abstract
Original language | English |
---|---|
Article number | 2481 |
Journal | Nature communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2023 |
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In: Nature communications, Vol. 14, No. 1, 2481, 01.12.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome
AU - Barry, Alexandra
AU - McNulty, Michelle T.
AU - Jia, Xiaoyuan
AU - Gupta, Yask
AU - Debiec, Hanna
AU - Luo, Yang
AU - Nagano, China
AU - Horinouchi, Tomoko
AU - Jung, Seulgi
AU - Colucci, Manuela
AU - Ahram, Dina F.
AU - Mitrotti, Adele
AU - Sinha, Aditi
AU - Teeninga, Nynke
AU - Jin, Gina
AU - Shril, Shirlee
AU - Caridi, Gianluca
AU - Bodria, Monica
AU - Lim, Tze Y.
AU - Westland, Rik
AU - Zanoni, Francesca
AU - Marasa, Maddalena
AU - Turudic, Daniel
AU - Giordano, Mario
AU - Gesualdo, Loreto
AU - Magistroni, Riccardo
AU - Pisani, Isabella
AU - Fiaccadori, Enrico
AU - Reiterova, Jana
AU - Maringhini, Silvio
AU - Morello, William
AU - Montini, Giovanni
AU - Weng, Patricia L.
AU - Scolari, Francesco
AU - Saraga, Marijan
AU - Tasic, Velibor
AU - Santoro, Domenica
AU - van Wijk, Joanna A. E.
AU - Milošević, Danko
AU - Kawai, Yosuke
AU - Kiryluk, Krzysztof
AU - Pollak, Martin R.
AU - Gharavi, Ali
AU - Lin, Fangmin
AU - Simœs e Silva, Ana Cristina
AU - Loos, Ruth J. F.
AU - Kenny, Eimear E.
AU - Schreuder, Michiel F.
AU - Zurowska, Aleksandra
AU - Dossier, Claire
AU - Ariceta, Gema
AU - Drozynska-Duklas, Magdalena
AU - Hogan, Julien
AU - Jankauskiene, Augustina
AU - Hildebrandt, Friedhelm
AU - Prikhodina, Larisa
AU - Song, Kyuyoung
AU - Bagga, Arvind
AU - Cheong, Hae
AU - Ghiggeri, Gian Marco
AU - Vachvanichsanong, Prayong
AU - Nozu, Kandai
AU - Lee, Dongwon
AU - Vivarelli, Marina
AU - Raychaudhuri, Soumya
AU - Tokunaga, Katsushi
AU - Sanna-Cherchi, Simone
AU - Ronco, Pierre
AU - Iijima, Kazumoto
AU - Sampson, Matthew G.
N1 - Funding Information: K.I., K.N., and K.T. were supported by the Japan Agency for Medical Research and Development (AMED) under grant number JP17km0405108h0005. K.T. was supported by the Japan Agency for Medical Research and Development (AMED) under grants JP17km0405205h0002 and 18km0405205h0003. K.I., T.H., C.N., and K.N. were supported by the Japan Society for the Promotion of Science (JSPS) under Grant-in-Aid for Scientific Research fostering Joint International Research (B) 18KK0244. K.I., X.J., T.H., C.N., and K.N. were supported by the Japan Society for the Promotion of Science (JSPS) under Grant-in-Aid for Scientific Research fostering Joint International Research (B) 21KK0147. This work is supported by the Department of Defense (PR190746, PR212415) to S.S-C., by the National Center for Advancing Translational Sciences, National Institutes of Health (Grant Number UL1TR001873) to S.S-C., and by the National Institute of Health Grant RC2DK122397, M.Sam, S.S-C., M.R.P., and F.H. A.M. received support from the American Society of Nephrology KidneyCure Ben J. Lipps Research Fellowship. Y.G. received support from the NEPTUNE Career Development Award. P.R. and H.D. were funded by European Research Council grant ERC-2012- ADG_20120314 (grant agreement 322947) and Agence Nationale pour la Recherche “Genetransnephrose” grant ANR-16-CE17-004-01. M.Sam. was supported by NIH grants R01DK119380, 2U54DK083912, and a gift from The Pura Vida Kidney Foundation. The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support is provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center (DMCC), funded by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS) under U2CTR002818. The authors wish to thank Seong Kyu Han, Ph.D. (Boston Children’s Hospital and Harvard Medical School) for his assistance in creating figures. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85156168251&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-37985-w
DO - https://doi.org/10.1038/s41467-023-37985-w
M3 - Article
C2 - 37120605
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2481
ER -