Genome-wide association studies identify the role of caspase-9 in kidney disease.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34739325.
- Also identified by DOI 10.1126/sciadv.abi8051 and PMC identifier 8570608.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Genome-wide association studies (GWAS) have identified hundreds of genetic risk regions for kidney dysfunction [estimated glomerular filtration rate (eGFR)]; however, the causal genes, cell types, and pathways are poorly understood. Integration of GWAS and human kidney expression of quantitative trait analysis using Bayesian colocations, transcriptome-wide association studies, and summary-based Mendelian randomization studies prioritized caspase-9 (CASP9) as a kidney disease risk gene. Human kidney single-cell epigenetic and immunostaining studies indicated kidney tubule cells as a disease-causing cell type. Mice with genetic deletion or pharmacological inhibition of CASP9 showed lower apoptosis while having improved mitophagy, resulting in dampened activation of cytosolic nucleotide sensing pathways (cGAS-STING), reduction of inflammation, and protection from acute kidney disease or renal fibrosis. In summary, here, we prioritized CASP9 as an eGFR GWAS target gene and demonstrated the causal role of CASP9 in kidney disease development via improving mitophagy and lowering inflammation and apoptosis.