Little evidence for an effect of smoking on multiple sclerosis risk: A Mendelian Randomization study.
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ABSTRACT:
SUBMITTER: Mitchell RE
PROVIDER: S-EPMC7728259 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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Little evidence for an effect of smoking on multiple sclerosis risk: A Mendelian Randomization study.
Mitchell Ruth E RE Bates Kirsty K Wootton Robyn E RE Harroud Adil A Richards J Brent JB Davey Smith George G Munafò Marcus R MR
PLoS biology 20201130 11
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). T ...[more]
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Project description:ObjectiveTo investigate the potential for a causal effect of age at puberty on multiple sclerosis (MS) susceptibility using a mendelian randomization (MR) approach.MethodsWe used 372 genetic variants strongly associated with age at menarche in a genome-wide association study (GWAS) involving 329,245 women. The genetic architecture of pubertal timing across both sexes is highly correlated (genetic correlation [r g] = 0.75, p = 1.2 × 10-79), allowing these variants to provide reliable insight into pubertal timing in males as well. The effect of pubertal timing on risk of MS was measured with summary statistics from a GWAS of 14,802 cases with MS and 26,703 controls from the International Multiple Sclerosis Genetics Consortium. Multivariable MR controlling for effects of body mass index (BMI) using genetic data from additional consortia investigated whether pubertal effects on MS were dependent on weight status.ResultsA 1-year increase in genetically predicted age at puberty decreased odds of MS by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86-0.99, p = 0.03). However, multivariable MR analysis showed that after accounting for effects on adult BMI, the association of age at puberty with MS susceptibility attenuated (OR 0.96, 95% CI 0.88-1.04, p = 0.36). Similar results were obtained when childhood BMI was incorporated. Sensitivity analyses provided no evidence of major bias from genetic pleiotropy.ConclusionsWe found support for an association between higher age at puberty and decreased risk of MS with a magnitude comparable to that reported in observational studies. This effect appears to be largely mediated by the strong association between age at puberty and obesity. A large causal effect of pubertal timing independent of BMI is unlikely.
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Project description:BackgroundObservational studies and previous Mendelian randomization (MR) studies have shown that genetically low 25-hydroxyvitamin D (25OHD) levels are associated with a high susceptibility to multiple sclerosis (MS). The present MR study aims to update the causal estimates for the effects of 25OHD levels on MS risk.MethodsTo date, the largest genome-wide association study (GWAS) for serum 25OHD (n = 401,460) and MS (14,498 MS cases and 24,091 controls) was used to assess the effect of serum 25OHD levels on MS. All participants were of European ancestry. The MR-egger_intercept test and Cochran's Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. MR-egger, weighted median, inverse variance weighted (multiplicative random effects), simple mode, and weighted mode methods were used to evaluate the causal association of serum 25OHD levels with MS. Finally, the effect of a single 25OHD SNP (single nucleotide polymorphism) on MS was used to test the SNP bias.ResultsOne hundred and fifteen newly identified serum 25OHD genetic variants were extracted from a large-scale serum 25OHD GWAS dataset. The 20 most effective and independent 25OHD genetic instrumental variables were extracted from the MS GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 20 selected 25OHD genetic instrument variants in MS GWAS datasets. As serum levels of 25OHD based on genetic changes increased, the risk of MS decreased using MR-egger (Beta = - 0.940, p = 0.001; OR = 0.391), weighted median (Beta = - 0.835, p = 0.000; OR = 0.434), IVW (Beta = - 0.781, p = 0.000; OR = 0.458), simple mode (Beta = - 1.484, p = 0.016; OR = 0.227), and weighted mode (Beta = - 0.913, p = 0.000; OR = 0.401). Our results were robust, with no obvious bias based on investigating the single 25OHD SNP on MS.ConclusionsOur analysis suggested a causal association between genetically increased serum 25OHD levels and reduced MS in the European population.
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Project description:ObjectivesMultiple sclerosis (MS) is a complex central nervous system (CNS) demyelinating disease, the etiology of which involves the interplay between genetic and environmental factors. We aimed to determine whether genetically predicted peripheral immune cell counts may have a causal effect on MS.MethodsWe used genetic variants strongly associated with cell counts of circulating leukocyte, lymphocyte, monocyte, neutrophil, eosinophil, and basophil, in addition to some subpopulations of T and B lymphocyte, as instrumental variables (IVs) to perform Mendelian randomization (MR) analyses. The effect of immune cell counts on MS risk was measured using the summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) genome-wide association studies (GWAS).ResultsOur findings indicated that higher leucocyte count [odds ratio (OR), 1.24; 95% confidence interval (CI), 1.07 - 1.43; p = 0.0039] and lymphocyte count (OR, 1.17; 95% CI, 1.01 - 1.35; p = 0.0317) were causally associated with MS susceptibility. In addition, we also found that increase of genetically predicted natural killer T (NKT) cell count is also associated with an increase MS risk (OR, 1.24; 95% CI, 1.06 - 1.45; p = 0.0082).ConclusionsThese findings show that the genetic predisposition to higher peripheral immune cell counts can exert a causal effect on MS risk, which confirms the crucial role played by peripheral immunity in MS. Particularly, the causal association between NKT cell count and MS underscores the relevance of exploring the functional roles of NKT cells in disease pathogenesis in future.
| S-EPMC9128528 | biostudies-literature