Kiryluk, Krzysztof;
Sanchez-Rodriguez, Elena;
Zhou, Xu-Jie;
Zanoni, Francesca;
Liu, Lili;
Mladkova, Nikol;
Khan, Atlas;
... Gharavi, Ali G; + view all
(2023)
Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy.
Nature Genetics
, 55
(7)
pp. 1091-1105.
10.1038/s41588-023-01422-x.
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2023 Kiryluk IgAN GWAS and targets Nat Genet Submitted.pdf - Accepted Version Download (17MB) | Preview |
Abstract
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
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