Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

Journal Article (Journal Article)

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Full Text

Duke Authors

Cited Authors

  • Jia, X; Yamamura, T; Gbadegesin, R; McNulty, MT; Song, K; Nagano, C; Hitomi, Y; Lee, D; Aiba, Y; Khor, S-S; Ueno, K; Kawai, Y; Nagasaki, M; Noiri, E; Horinouchi, T; Kaito, H; Hamada, R; Okamoto, T; Kamei, K; Kaku, Y; Fujimaru, R; Tanaka, R; Shima, Y; Research Consortium on Genetics of Childhood Idiopathic Nephrotic Syndrome in Japan, ; Baek, J; Kang, HG; Ha, I-S; Han, KH; Yang, EM; Korean Consortium of Hereditary Renal Diseases in Children, ; Abeyagunawardena, A; Lane, B; Chryst-Stangl, M; Esezobor, C; Solarin, A; Midwest Pediatric Nephrology Consortium (Genetics of Nephrotic Syndrome Study Group), ; Dossier, C; Deschênes, G; NEPHROVIR, ; Vivarelli, M; Debiec, H; Ishikura, K; Matsuo, M; Nozu, K; Ronco, P; Cheong, HI; Sampson, MG; Tokunaga, K; Iijima, K

Published Date

  • November 2020

Published In

Volume / Issue

  • 98 / 5

Start / End Page

  • 1308 - 1322

PubMed ID

  • 32554042

Pubmed Central ID

  • PMC8101291

Electronic International Standard Serial Number (EISSN)

  • 1523-1755

Digital Object Identifier (DOI)

  • 10.1016/j.kint.2020.05.029


  • eng

Conference Location

  • United States