Genetic prediction of micronutrient levels and the risk of multiple system atrophy: a two-sample Mendelian randomization study

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder of elusive pathogenesis, and observational links to micronutrients are prone to confounding. Mendelian randomization (MR) uses genetic variants as instrumental variables to infer causality, minimizing confounding and reverse causation by mimicking randomized controlled trials. We performed a two-sample MR analysis using summary statistics from large-scale genome-wide association studies. Genetic instruments for 16 micronutrients (iron, copper, calcium, magnesium, potassium, selenium, zinc, carotene, folate, fish oil, retinol and vitamins B6, B12, C, D, E) were selected at a genome-wide significance threshold. The primary analysis used the inverse variance weighted method, supplemented by the weighted median, simple mode, weighted mode and MR-Egger regression methods. Sensitivity analyses (Cochran’s Q test, MR-Egger intercept, MR-PRESSO and leave-one-out analysis) assessed heterogeneity and pleiotropy. No causal effects of genetically predicted levels of the 16 micronutrients on MSA risk were found. Sensitivity analyses revealed no significant heterogeneity or pleiotropy. Statistical power was sufficient to detect modest effects. The findings suggest that altered micronutrient levels in MSA patients are likely consequences, not causes, of the disease. This redirects therapeutic focus away from supplementation of these specific nutrients and towards other molecular pathways in MSA.