Kiryluk, Krzysztof; Sanchez-Rodriguez, Elena; Zhou, Xu-Jie; Zanoni, Francesca; Liu, Lili; Mladkova, Nikol; Khan, Atlas; Marasa, Maddalena; Zhang, Jun Y; Balderes, Olivia; Sanna-Cherchi, Simone; Bomback, Andrew S; Canetta, Pietro A; Appel, Gerald B; Radhakrishnan, Jai; Trimarchi, Hernan; Sprangers, Ben; Cattran, Daniel C; Reich, Heather; Pei, York; ... (2023). Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nature genetics, 55(7), pp. 1091-1105. Springer Nature 10.1038/s41588-023-01422-x
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension |
UniBE Contributor: |
Vogt, Bruno, Mani, Laila-Yasmin |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1546-1718 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
20 Jun 2023 12:08 |
Last Modified: |
13 Jul 2023 00:15 |
Publisher DOI: |
10.1038/s41588-023-01422-x |
PubMed ID: |
37337107 |
BORIS DOI: |
10.48350/183544 |
URI: |
https://boris.unibe.ch/id/eprint/183544 |
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