Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
Nature Genetics(2023)
摘要
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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关键词
Genome-wide association studies,IgA nephropathy,Biomedicine,general,Human Genetics,Cancer Research,Agriculture,Gene Function,Animal Genetics and Genomics
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