Roles of cerebrospinal fluid metabolites in mediating the relationship between cathepsins and narcolepsy type 1: A comprehensive Mendelian randomization analysis

Introduction

To investigate the potential causal relationship between cathepsins and Narcolepsy Type 1 (NT1), along with the mediating influence of cerebrospinal fluid metabolites.

Method

We performed a comprehensive Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) data. Data on nine plasma cathepsins and 338 cerebrospinal fluid metabolites were sourced from the IEU OpenGWAS database, and NT1 were obtained from the FinnGen consortium's R10 release. Univariate MR (UVMR), multivariate MR (MVMR) and gene co-localization analyses were used to explore the potential causal relationship between cathepsins and NT1. In addition, mediation analyses were performed to explore the role of cerebrospinal fluid metabolites in mediating the relationship.

Result

In UVMR study, we identified a significant positive association between genetically elevated levels of plasma cathepsin B (OR = 2.022, 95 % CI: 1.456–2.809, p < 0.01) and cathepsin F (OR = 0.676, 95 % CI: 0.473–0.966, p = 0.031) with NT1. However, in the MVMR analysis, only cathepsin B maintained a consistent effect (OR = 1.920, 95 % CI: 1.378–2.675, p < 0.001). Subsequent co-localization analysis indicated shared causal variants between cathepsin B and NT1, further highlighting the robustness of our findings. Additionally, mediation MR revealed that the association between cathepsin B and NT1 was mediated by sphingomyelin and 1-(1-alkenyl-palmitoyl1)-2-propenoyl-gpc, accounting for 2.6 % and 4.7 % of the effect, respectively.

Conclusion

Our findings suggest a probable causal relationship between increased cathepsin B levels and NT1, with the potential of cerebrospinal fluid fatty acid metabolism disorder playing a mediating role in the development of this association. This indicates the potential of cathepsin B as a promising biomarker for NT1, highlighting significant implications for the diagnosis and treatment of this condition.