Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome. / Barry, Alexandra; McNulty, Michelle T.; Jia, Xiaoyuan; Gupta, Yask; Debiec, Hanna; Luo, Yang; Nagano, China; Horinouchi, Tomoko; Jung, Seulgi; Colucci, Manuela; Ahram, Dina F.; Mitrotti, Adele; Sinha, Aditi; Teeninga, Nynke; Jin, Gina; Shril, Shirlee; Caridi, Gianluca; Bodria, Monica; Lim, Tze Y.; Westland, Rik; Zanoni, Francesca; Marasa, Maddalena; Turudic, Daniel; Giordano, Mario; Gesualdo, Loreto; Magistroni, Riccardo; Pisani, Isabella; Fiaccadori, Enrico; Reiterova, Jana; Maringhini, Silvio; Morello, William; Montini, Giovanni; Weng, Patricia L.; Scolari, Francesco; Saraga, Marijan; Tasic, Velibor; Santoro, Domenica; van Wijk, Joanna A.E.; Milošević, Danko; Kawai, Yosuke; Kiryluk, Krzysztof; Pollak, Martin R.; Gharavi, Ali; Lin, Fangmin; Simœs e Silva, Ana Cristina; Loos, Ruth J.F.; Kenny, Eimear E.; Schreuder, Michiel F.; Zurowska, Aleksandra; Dossier, Claire; Ariceta, Gema; Drozynska-Duklas, Magdalena; Hogan, Julien; Jankauskiene, Augustina; Hildebrandt, Friedhelm; Prikhodina, Larisa; Song, Kyuyoung; Bagga, Arvind; Cheong, Hae; Ghiggeri, Gian Marco; Vachvanichsanong, Prayong; Nozu, Kandai; Lee, Dongwon; Vivarelli, Marina; Raychaudhuri, Soumya; Tokunaga, Katsushi; Sanna-Cherchi, Simone; Ronco, Pierre; Iijima, Kazumoto; Sampson, Matthew G.
I: Nature Communications, Bind 14, Nr. 1, 2481, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
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.
U2 - 10.1038/s41467-023-37985-w
DO - 10.1038/s41467-023-37985-w
M3 - Journal article
C2 - 37120605
AN - SCOPUS:85156168251
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2481
ER -
ID: 351001802