Causal relationship between metabolites, cerebral volume, and amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration. Although metabolic abnormalities have been implicated in ALS, the causal relationships between circulating metabolites and ALS remain unclear. This study aimed to investigate the potential causal associations between plasma metabolites and ALS risk and to explore the mediating role of cerebral volume. A 2-sample Mendelian randomization (MR) study was conducted using publicly available genome-wide association study summary statistics. Genetic instruments for plasma metabolites were obtained from metabolomic GWAS datasets, and ALS-associated genetic data were used as the outcome. The inverse-variance weighted method was used as the primary analysis, with sensitivity analyses performed using MR-Egger regression, weighted median analysis, MR-PRESSO, heterogeneity testing, and leave-one-out analysis. A 2-step MR analysis was further conducted to evaluate whether cerebral volume mediated the associations between metabolites and ALS. Six metabolites showed significant associations with ALS risk. Genetically predicted higher levels of N , N -dimethylalanine, Behenylcarnitine (C22), and deoxycarnitine were associated with increased ALS risk, whereas higher levels of (N(1) + N(8))-acetylspermidine, Betaine, and tetradecadienedioate (C14:2-DC) were associated with decreased ALS risk. Sensitivity analyses supported the robustness of the findings. Two-step MR analysis suggested that cerebral volume did not significantly mediate the associations between these metabolites and ALS risk. This study identified 6 circulating metabolites genetically associated with ALS risk. These findings provide insights into the potential metabolic pathways involved in ALS and suggest that the observed associations are unlikely to be mediated through cerebral volume changes.