Causality of blood metabolites and narcolepsy type 1: A Mendelian randomization study

Metabolic disturbances have been implicated in narcolepsy type 1 (NT1), but the causal relationships between circulating metabolites and NT1 remain unclear. A two-sample bidirectional Mendelian randomization (MR) analysis was conducted to explore potential causal associations between 486 blood metabolites (7824 Europeans) and NT1. Genetic instruments were selected from large-scale genome-wide association study summary statistics under strict thresholds (P < 1 × 10-5, r2 < 0.001, F > 10). NT1 data were obtained from the R12 release of the FinnGen consortium. The inverse variance weighted method served as the primary estimator, complemented by MR-Egger regression, weighted median, heterogeneity, and pleiotropy assessments (including MR-Pleiotropy RESidual Sum and Outlier), and leave-one-out analysis. Reverse MR was performed to examine the potential effect of NT1 on metabolite levels. A total of 21 blood metabolites showed suggestive causal associations with NT1. Among the known metabolites, aspartate, 2-hydroxystearate, N-acetylglycine, and phenol sulfate were positively associated with NT1 risk, while indoleacetate, acetylcarnitine, caproate (6:0), docosapentaenoate (n3 DPA; 22:5n3), homostachydrine*, hydroquinone sulfate, 4-ethylphenylsulfate, 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-Hoca), 4-androsten-3beta, 17beta-diol disulfate 2*, and 2-hydroxyglutarate exhibited inverse associations. Reverse MR analysis did not identify significant effects of NT1 on metabolite levels. This MR study identified multiple metabolites potentially associated with NT1, providing preliminary genetic evidence for the involvement of metabolic pathways in NT1 pathogenesis. These findings highlight the possible biological links between metabolic dysregulation and NT1 and lay a foundation for future large-scale and experimental studies to confirm their causal roles.