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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 …