Genetic and metabolomic pathways linking frailty, chronic kidney disease, and kidney failure: a Mendelian randomization and multi-omics analysis.

Global population aging highlights frailty as a critical health concern, yet its genetic basis remains poorly understood. We employed Mendelian randomization (MR) and National Health and Nutrition Examination Survey (NHANES) to examine causal relationships between frailty index (FI) and 36 urological diseases, investigating shared genetic mechanisms. The FI was calculated using genome-wide association data, and bidirectional MR analysis with multiple statistical methods was applied to investigate causal links between FI and 36 urological diseases. Complementary observational analyses using NHANES and generalized summary MR validation were conducted, followed by genetic correlation assessments, genome annotation, and metabolomic explorations to identify mediating pathways. MR analysis identified a significant causal association between FI and renal tubule-interstitial disease, chronic kidney diseases (CKDs), diabetes with renal complications, renal failure, and acute kidney injury. Reverse MR analysis indicated a bidirectional causal relationship between FI and acute renal failure, as well as CKD and type 1 diabetic kidney disease. NHANES data confirmed FI as an independent risk factor for CKD and renal failure. Genetic linkage analyses identified strong regional correlations between FI and CKD/renal failure within the chromosome 6 locus (31,571,218-32,682,664). Genome-wide analyses uncovered 103 novel single-nucleotide polymorphism with pleiotropic effects on the frailty-urinary disease relationship. Mediation analyses implicated the complement pathway (C2), SLITRK1, and 4-methylhexanoylglutamine as putative mediators of FI effects on CKD and kidney failure. This study elucidates the bidirectional causal relationship between frailty and CKD, while identifying novel genetic variants and metabolic pathways. These findings provide a molecular basis for developing personalized therapeutic strategies targeting both frailty and urological disorders.