Abstract: Objective To investigate the causal relationship between the nine cathepsins and frailty index at the genetic level using the bidirectional two-sample Mendelian randomization(TSMR), so as to provide new insights for future prevention and treatment strategies for frailty. Methods Genome-wide association study(GWAS)summary data for nine cathepsins(B, E, F, G, H, L2, O, S, and Z)were obtained from the INTERVAL study, which included 3,301 European participants, and GWAS summary data for frailty index were obtained from the meta-analyses including 164,610 UK Biobank and 10,616 Swedish TwinGene participants. TSMR analysis was conducted using inverse variance weighted(IVW)as the primary method, and two regression models, including MR-Egger and weighted median, as the supplementary. In addition, horizontal pleiotropy was tested using the MR-Egger intercept test and MR-pleiotropy residual sum and outliers(MR-PRESSO)analysis, heterogeneity was assessed by applying Cochrans Q test in MR-Egger and IVW methods, and sensitivity analysis was performed using the “leave-one-out” method. Finally, reverse TSMR analysis was used to verify the robustness of the results. Results The forward TSMR analysis corrected by the Bonferroni method revealed a causal relationship between genetically predicted elevated serum cathepsin E level and higher frailty index(β=0.033, 95%CI:0.015-0.050, P<0.001). The reverse TSMR analysis revealed no causal relationship between genetically predicted frailty index and various types of cathepsins(P>0.05/3). The MR-Egger regression model intercept term test, MR-PRESSO Global test and Cochrans Q test showed that the screened single nucleotide polymorphism(SNP)did not have horizontal pleiotropy or heterogeneity. Sensitivity analysis based on the “leave-one-out” method showed that a single SNP did not affect the robustness of the causal association effect values. Conclusion At the genetic level, cathepsin E could potentially serve as a predictive biomarker for susceptibility to frailty, providing new insights for basic and clinical studies of frailty and possible interventions.

Key words: Cathepsins, Frailty, Mendelian randomization, Genome-wide association study