Genetically predicted cerebrospinal fluid metabolite levels and risk of sudden sensorineural hearing loss: A Mendelian randomization study

Sudden sensorineural hearing loss (SSNHL) is an idiopathic condition lacking reliable biomarkers or established causal mechanisms. While systemic metabolic dysregulation has been implicated, the specific role of central nervous system metabolites remains unexplored. We applied a 2-sample Mendelian randomization framework to evaluate the causal influence of cerebrospinal fluid (CSF) metabolites on SSNHL risk. Genetic instruments for 338 metabolites were derived from a European-ancestry genome-wide association study (n = 689), and outcome data came from the FinnGen Consortium (3861 cases; 437,331 controls). Analysis employed inverse-variance weighted regression as the primary method, alongside sensitivity and pleiotropy-robust methods. Inverse-variance weighted analysis identified 20 metabolites with suggestive associations ( P  < .05). After excluding 1 metabolite due to potential reverse causation effects identified in sensitivity analysis, 19 metabolites were retained for subsequent investigation. Causal risk factors included cholesterol (odds ratio [OR] = 1.08, P   =  .032), alpha-ketoglutarate (OR = 1.28, P   =  .001), and malate (OR = 1.56, P =  .018). Protective metabolites included isoleucine (OR = 0.80, P   =  .036) and trimethylamine N-oxide (OR = 0.93, P   =  .023). Sensitivity analyses and reverse Mendelian randomization ruled out confounding or reverse causation. Pathway analysis implicated the citrate cycle, branched-chain amino acid biosynthesis, and ascorbate metabolism. These results provide suggestive evidence for a potential causal link between CSF metabolites and SSNHL, highlighting the role of central energy metabolism and oxidative balance in auditory function. Our findings suggest that CSF metabolites may represent potential biomarkers and highlight the potential for CSF-mediated interventions in hearing loss.