Fig 1.
(A) Directed acyclic graph of the MR framework investigating the causal relationship between smoking and MS. Instrumental variable assumptions: (1) the instruments must be associated with the exposure; (2) the instruments must influence MS only through smoking; and (3) the instruments must not associate with measured or unmeasured confounders in the smoking to MS relationship. (B and C) Flowchart for selection of genetic variants associated with smoking initiation (B) and lifetime smoking (C). GSCAN, GWAS & Sequencing Consortium of Alcohol and Nicotine use; GWAS, genome-wide association study; IMSGC, International Multiple Sclerosis Genetics Consortium; IV, instrumental variable; LD, linkage disequilibrium; MR, Mendelian randomization; MS, multiple sclerosis; OR, odds ratio; SNP, single nucleotide polymorphism.
Fig 2.
Two-sample MR estimates of the association between smoking initiation and the incidence of MS.
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.
Fig 3.
Two-sample MR estimates of the association between lifetime smoking and the incidence of MS.
A two-sample MR analysis was undertaken to obtain causal estimates of genetically predicted lifetime smoking 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 1 SD increase of the lifetime smoking index. A SD increase in the lifetime smoking score is equivalent to an individual smoking 20 cigarettes a day for 15 years and stopping 17 years ago or an individual smoking 60 cigarettes a day for 13 years and stopping 22 years ago. The genetic variants used to proxy lifetime smoking are the independent genome-wide significant SNPs taken from the GWAS of lifetime smoking performed by Wootton and colleagues detailed in Table C in S1 Data. The estimates of their association with MS are taken from the 2019 MS Chip IMSGC meta-analysis. CI, confidence interval; GWAS, genome-wide association study; 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.