A two-sample MR analysis was undertaken to obtain causal estimates of genetically predicted smoking initiation on MS susceptibility. MR and sensitivity analyses were performed using the TwoSampleMR R package with a comparison across 5 different methods. ORs are expressed per unit increase in log odds of ever smoking regularly (smoking initiation), with a 1 SD increase in genetically predicted smoking initiation corresponding to a 10% increased risk of smoking. The genetic variants used to proxy smoking initiation are the conditionally independent genome-wide significant SNPs taken from the GSCAN consortium detailed in Table A in S1 Data. The estimates of their association with MS are taken from the 2019 MS Chip IMSGC meta-analysis. CI, confidence interval; GSCAN, GWAS & Sequencing Consortium of Alcohol and Nicotine use; IMSGC, International Multiple Sclerosis Genetics Consortium; MR, Mendelian randomization; MS, multiple sclerosis; OR, odds ratio; p.val, p-value; RAPS, robust adjusted profile score; SD, standard deviation; SNP, single nucleotide polymorphism.