Abstract
The causes of multiple sclerosis (MS) remain unknown. Smoking has been associated with MS in observational studies and is often thought of as an environmental risk factor. We used two-sample Mendelian randomization (MR) to examine whether this association is causal using genetic variants identified in genome-wide association studies (GWASs) as associated with smoking. We assessed both smoking initiation and lifetime smoking behaviour (which captures smoking duration, heaviness, and cessation). There was very limited evidence for a meaningful effect of smoking on MS susceptibility as measured using summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) meta-analysis, including 14,802 cases and 26,703 controls. There was no clear evidence for an effect of smoking on the risk of developing MS (smoking initiation: odds ratio [OR] 1.03, 95% confidence interval [CI] 0.92-1.61; lifetime smoking: OR 1.10, 95% CI 0.87-1.40). These findings suggest that smoking does not have a detrimental consequence on MS susceptibility. Further work is needed to determine the causal effect of smoking on MS progression.
Highlights
Smoking is an avoidable environmental cause to many life-threatening diseases such as lung cancer and heart and respiratory disorders [1,2]
Mendelian randomization (MR)-robust adjusted profile score (RAPS) is robust to systematic and idiosyncratic pleiotropy, accounting for weak instruments, pleiotropy, and extreme outliers and gave a similar causal estimate
MR-pleiotropy residual sum and outlier (PRESSO) removes individual outlier single nucleotide polymorphism (SNP) that contribute to heterogeneity disproportionately in order to correct for horizontal pleiotropy
Summary
Smoking is an avoidable environmental cause to many life-threatening diseases such as lung cancer and heart and respiratory disorders [1,2]. There is emerging evidence linking cigarette smoke to conditions negatively affecting the central nervous system (CNS), like multiple sclerosis (MS) [3,4]. Multiple Sclerosis GWAS summary data is available from the International Multiple Sclerosis Genetics Consortium (IMSGC) upon person validation and agreement not to distribute data to third parties at https://imsgc.net/?page_id= 31
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