Chronic kidney disease (CKD) is increasingly recognized as a major global health burden, with neurological manifestations, such as cognitive impairment and depression contributing significantly to patient disability. However, the underlying mechanisms associated with cognitive impairment in CKD remain poorly understood. We conducted a genome-wide association study (GWAS) using CKD-adjusted cognitive function measurements as a phenotype using data from the UK Biobank. Also, we performed single-nucleus RNA sequencing (snRNA-seq) of the cerebral cortex to investigate the mechanisms of cognitive impairment in CKD patients using a rat CKD model (5/6 nephrectomy). We found 1,880 single nucleotide polymorphisms (SNPs) that were genome-wide significant level (P < 5 x 10-8) (Figure 1A). Fine-mapping studies, including FUMA (mapping using position, eQTL, and chromatin accessibility), H-MAGMA, and TWAS, were performed, resulting in 14 genes (Figure 1B). The partitioned heritability calculated using LD score regression showed that significant SNPs were enriched in brain tissue, especially in the cerebral cortex (Figure 1C). Therefore, we performed snRNA-seq using the cerebral cortex from 5/6 nephrectomized and sham rats (Figure 2A). The differentially expressed genes (DEGs) were enriched in astrocytes rather than in other brain cell types (Figure 2B). Trajectory analysis revealed that CKD-specific astrocytes (cluster 5 in Figure 2C-E) play an important role in the pathogenesis of cognitive impairment in CKD (Figure 2C). The DEGs in cluster 5 astrocytes included some genes that discovered by GWAS (Figure 2D). The cluster 5 astrocytes, CKD-specific astrocytes, showed enriched pathways associated with several synaptic and signaling pathways (Figure 2E). We leveraged the GWAS results using the UK Biobank and snRNA­-seq of CKD rats to uncover the molecular and cellular mechanisms underlying CKD-related cognitive impairment and highlight the role of CKD-specific astrocyte population in this process. Our study provides new insights into the pathogenesis of cognitive decline in CKD.