A metabolome-wide Mendelian randomization study prioritizes potential causal circulating metabolites for multiple sclerosis (Supplementary Files)

<strong>Objective:</strong> To prioritize circulating metabolites that likely play causal roles in the pathogenesis of multiple sclerosis (MS). <strong>Methods: </strong>We performed a two-sample Mendelian randomization analysis of 571 circulating metabolites using genetic instruments from three genome-wide association studies (GWAS) of the blood metabolome (N=7,824; 24,925; and 115,078; respectively). Genetic associations with MS were from a large GWAS by the International Multiple Sclerosis Genetics Consortium (14,802 cases and 26,703 control). The primary analysis was performed with the multiplicative random-effect inverse variance-weighted method, while multiple sensitivity analyses were also conducted. <strong>Results: </strong>A total of 29 metabolites were prioritized for causal associations with MS. Genetically instrumented levels of serine (OR=1.56, 95% CI=1.25–1.95), lysine (OR=1.18, 95% CI=1.01–1.38), acetone (OR=2.45, 95% CI=1.02–5.90), and acetoacetate (OR=2.47, 95% CI=1.14–5.34) were associated with a higher MS risk. Total cholesterol and phospholipids in large very-low-density lipoprotein were associated with a lower MS risk (OR=0.83, 95% CI=0.69–1.00; OR=0.80, 95% CI=0.68–0.95), but the same two lipids in very large high-density lipoprotein have risk-increasing associations (OR=1.20, 95% CI=1.04–1.40; OR=1.13, 95% CI=1.00–1.28). <strong>Conclusions: </strong>Our metabolome-wide Mendelian randomization study prioritized 29 circulating metabolites, such as serine, lysine, acetone, acetoacetate, and lipids, that likely have causal associations with MS.