No evidence for a causal link between plasma lipids and multiple sclerosis susceptibility and severity: a Mendelian randomisation study

Observational studies suggest that alterations in circulating lipid levels may be associated with multiple sclerosis (MS) susceptibility and severity. Our study employs two-sample Mendelian randomization (MR) to investigate whether these relationships are causal. Genetic instruments for 249 metabolites, predominantly lipids and lipoproteins, were obtained from a combined dataset of European-ancestry individuals from the UK and Estonian Biobanks. Outcome data were obtained from the International MS Genetics Consortium GWAS studies of MS susceptibility and severity. MR analyses considered MS susceptibility and severity as distinct outcomes and utilized the inverse variance-weighted multiplicative random-effects method in the main analysis. No metabolic exposures demonstrated statistically significant evidence of a causal relationship with MS susceptibility. For MS severity, two traits showed suggestive associations - triglycerides in very-low-density lipoproteins (VLDL) ({beta} = -0.101, SE = 0.028, p = 3.9 x 10-4) and triglycerides in chylomicrons and extremely large VLDL ({beta} = -0.104, SE = 0.032, p = 1.2 x 10-3). The MR-Egger intercept suggested that these observations may be driven by horizontal pleiotropy. Sensitivity analysis with multivariable MR using Body Mass Index as a possible confounder demonstrated substantial attenuation of instrument strength once genetic overlap with BMI was taken into account. In this study we found no convincing evidence that circulating lipids or lipid-related metabolites exert a causal influence on susceptibility to, or severity of, multiple sclerosis. The nominally statistically significant result is likely a result of horizontal pleiotropy.