scholarly journals Mendelian randomization in multiple sclerosis: A causal role for vitamin D and obesity?

2018 ◽  
Vol 24 (1) ◽  
pp. 80-85 ◽  
Author(s):  
Adil Harroud ◽  
J Brent Richards
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Disease Onset ◽  
Epidemiologic Studies ◽  
Causal Role ◽  
Complex Interplay ◽  
Genetic And Environmental Factors ◽  
Residual Confounding

The etiology of multiple sclerosis (MS) involves a complex interplay of genetic and environmental factors. Epidemiologic studies have furthered our understanding of these risk factors but remain limited by residual confounding and potential for reverse causation, particularly in MS where time of disease onset is not known. Mendelian randomization (MR) uses genetic variants to study the causal effect of modifiable exposures on an outcome. This method avoids some of the limitations of classical epidemiology and can strengthen causal inference. Here, we introduce the basic concepts of MR and review its contributions to the field of MS. Indeed, several studies using MR have now provided support for a causal role for low vitamin D level and obesity in the development of MS.

scholarly journals The causal role of circulating vitamin D concentrations in human complex traits and diseases: a large-scale Mendelian randomization study

2019 ◽  
Author(s):  
Xia Jiang ◽  
Tian Ge ◽  
Chia-Yen Chen
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Complex Traits ◽  
Large Scale ◽  
Randomized Clinical Trials ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
European Ancestry ◽  
Effect Estimate ◽  
Human Complex

AbstractVitamin D has been associated with a variety of human complex traits and diseases in observational studies, but a causal relationship remains unclear. To examine a putative causal effect of vitamin D across phenotypic domains and disease categories, we conducted Mendelian randomization (MR) analyses using genetic instruments associated with circulating 25-hydroxyvitamin D [25(OH)D] concentrations. We leveraged genome-wide significant 25(OH)D-associated SNPs (N=138) from a meta-analysis combining a vitamin D GWAS conducted in 401,460 white British UK Biobank (UKBB) participants and an independent vitamin D GWAS including 42,274 samples of European ancestry, and examined 190 large-scale health-related GWAS spanning a broad spectrum of complex traits, diseases and biomarkers. We applied multiple MR methods to estimate the causal effect of vitamin D while testing and controlling for potential biases from horizontal pleiotropy. Consistent with previous findings, genetically predicted increased 25(OH)D levels significantly decreased the risk of multiple sclerosis (OR=0.824; 95%CI=0.689-0.986). The protective effect estimate was consistent across different MR methods and four different multiple sclerosis GWAS with varying sample sizes and genotyping platforms. On the contrary, we found limited evidence in support of a causal effect of 25(OH)D on anthropometric traits, obesity, cognitive function, sleep behavior, breast and prostate cancer, and autoimmune, cardiovascular, metabolic, neurological and psychiatric traits and diseases, and blood biomarkers. Our results may inform ongoing and future randomized clinical trials of vitamin D supplementation.

scholarly journals Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk

2016 ◽  
Vol 2 (5) ◽  
pp. e97 ◽  
Author(s):  
Brooke Rhead ◽  
Maria Bäärnhielm ◽  
Milena Gianfrancesco ◽  
Amanda Mok ◽  
Xiaorong Shao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Multiple Sclerosis Risk

scholarly journals The causal role of circulating vitamin D concentrations in human complex traits and diseases: a large-scale Mendelian randomization study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xia Jiang ◽  
Tian Ge ◽  
Chia-Yen Chen
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Complex Traits ◽  
Large Scale ◽  
Randomized Clinical Trials ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
European Ancestry ◽  
Effect Estimate ◽  
Human Complex

AbstractVitamin D has been associated with a variety of human complex traits and diseases in observational studies, but a causal relationship remains unclear. To examine a putative causal effect of vitamin D across phenotypic domains and disease categories, we conducted Mendelian randomization (MR) analyses using genetic instruments associated with circulating 25-hydroxyvitamin D [25(OH)D] concentrations. We leveraged genome-wide significant 25(OH)D-associated SNPs (N = 138) from a meta-analysis combining a vitamin D GWAS conducted in 401,460 white British UK Biobank (UKBB) participants and an independent vitamin D GWAS including 42,274 samples of European ancestry, and examined 190 large-scale health-related GWAS spanning a broad spectrum of complex traits, diseases and biomarkers. We applied multiple MR methods to estimate the causal effect of vitamin D while testing and controlling for potential biases from horizontal pleiotropy. Consistent with previous findings, genetically predicted increased 25(OH)D levels significantly decreased the risk of multiple sclerosis (OR = 0.824; 95% CI 0.689–0.986). The protective effect estimate was consistent across different MR methods and four different multiple sclerosis GWAS with varying sample sizes and genotyping platforms. On the contrary, we found limited evidence in support of a causal effect of 25(OH)D on anthropometric traits, obesity, cognitive function, sleep behavior, breast and prostate cancer, and autoimmune, cardiovascular, metabolic, neurological and psychiatric traits and diseases, and blood biomarkers. Our results may inform ongoing and future randomized clinical trials of vitamin D supplementation.

scholarly journals Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

2021 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Kate Tilling ◽  
George Davey Smith ◽  
Deborah A Lawlor ◽  
Maria Carolina Borges
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Real Data ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

scholarly journals Supplementation and therapeutic use of vitamin D in patients with multiple sclerosis: Consensus of the Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology

2014 ◽  
Vol 72 (2) ◽  
pp. 152-156 ◽  
Author(s):  
Doralina Guimarães Brum ◽  
Elizabeth Regina Comini-Frota ◽  
Claúdia Cristina F. Vasconcelos ◽  
Elza Dias-Tosta
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Vitamin D ◽  
Environmental Factors ◽  
Scientific Evidence ◽  
Hypovitaminosis D ◽  
Central Nervous System Disease ◽  
Keywords Multiple Sclerosis ◽  
System Disease ◽  
Genetic And Environmental Factors

Multiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating, and degenerative central nervous system disease. Even though the etiology of MS has not yet been fully elucidated, there is evidence that genetic and environmental factors interact to cause the disease. Among the main environmental factors studied, those more likely associated with MS include certain viruses, smoking, and hypovitaminosis D. This review aimed to determine whether there is evidence to recommend the use of vitamin D as monotherapy or as adjunct therapy in patients with MS. We searched PUBMED, EMBASE, COCHRANNE, and LILACS databases for studies published until September 9 th , 2013, using the keywords “multiple sclerosis”, “vitamin D”, and “clinical trial”. There is no scientific evidence up to the production of this consensus for the use of vitamin D as monotherapy for MS in clinical practice.

scholarly journals The Causal Effect of Vitamin D Binding Protein (DBP) Levels on Calcemic and Cardiometabolic Diseases: A Mendelian Randomization Study

PLoS Medicine ◽  
2014 ◽  
Vol 11 (10) ◽  
pp. e1001751 ◽  
Author(s):  
Aaron Leong ◽  
Waheed Rehman ◽  
Zari Dastani ◽  
Celia Greenwood ◽  
Nicholas Timpson ◽  
...  
Keyword(s):  
Vitamin D ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Binding Protein ◽  
Vitamin D Binding Protein ◽  
Cardiometabolic Diseases

scholarly journals Using genetic variants to evaluate the causal effect of serum vitamin D concentration on COVID-19 susceptibility, severity and hospitalization traits: a Mendelian randomization study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhiyong Cui ◽  
Yun Tian
Keyword(s):  
Vitamin D ◽  
Fixed Effects ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Serum Vitamin ◽  
Vitamin D Supplementation ◽  
Sensitivity Analyses ◽  
Global Test ◽  
Serum Vitamin D

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has struck globally and is exerting a devastating toll on humans. The pandemic has led to calls for widespread vitamin D supplementation in public. However, evidence supporting the role of vitamin D in the COVID-19 pandemic remains controversial. Methods We performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effect of the 25-hydroxyvitamin D [25(OH)D] concentration on COVID-19 susceptibility, severity and hospitalization traits by using summary-level GWAS data. The causal associations were estimated with inverse variance weighted (IVW) with fixed effects (IVW-fixed) and random effects (IVW-random), MR-Egger, weighted edian and MR Robust Adjusted Profile Score (MR.RAPS) methods. We further applied the MR Steiger filtering method, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test and PhenoScanner tool to check and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. Results We found no evidence to support the causal associations between the serum 25(OH)D concentration and the risk of COVID-19 susceptibility [IVW-fixed: odds ratio (OR) = 0.9049, 95% confidence interval (CI) 0.8197–0.9988, p = 0.0473], severity (IVW-fixed: OR = 1.0298, 95% CI 0.7699–1.3775, p = 0.8432) and hospitalized traits (IVW-fixed: OR = 1.0713, 95% CI 0.8819–1.3013, p = 0.4878) using outlier removed sets at a Bonferroni-corrected p threshold of 0.0167. Sensitivity analyses did not reveal any sign of horizontal pleiotropy. Conclusions Our MR analysis provided precise evidence that genetically lowered serum 25(OH)D concentrations were not causally associated with COVID-19 susceptibility, severity or hospitalized traits. Our study did not provide evidence assessing the role of vitamin D supplementation during the COVID-19 pandemic. High-quality randomized controlled trials are necessary to explore and define the role of vitamin D supplementation in the prevention and treatment of COVID-19.

The global prevalence of familial multiple sclerosis: an updated systematic review and meta-analysis

2021 ◽  
Author(s):  
Naeim Ehtesham ◽  
Maryam Zare Rafie ◽  
Meysam Mosallaei
Keyword(s):  
Multiple Sclerosis ◽  
Web Of Science ◽  
Meta Analysis ◽  
Disease Onset ◽  
Inclusion Criteria ◽  
Multifactorial Diseases ◽  
Pooled Prevalence ◽  
Significant Difference ◽  
Meta Regression ◽  
Genetic And Environmental Factors

Abstract Background: Considering that familial multiple sclerosis (FMS) can reveal the extent to which genetic and environmental factors each involve in the etiopathogenesis of the disease, we performed an updated meta-analysis of the worldwide prevalence of FMS by addition of recent publications. Methods: A search in PubMed, Scopus, the ISI Web of Science, and Google Scholar up to 20 December 2020 was done. The inclusion criteria were based on the CoCoPop approach (condition, context, and population). The qualified studies entered the process of the meta-analysis by using comprehensive meta-analysis ver. 2 software.Results: The pooled prevalence of MS in relatives of 16179 FMS cases was estimated to be 11.8% (95% CI: 10.7-13) based on a random-effects model. The pooled mean age of disease onset in adult probands was calculated to be 28.7 years (95% CI: 27.2± 30.2). In 13 studies that reported the data of FMS in pediatrics (n=6636) and adults (n=877), the FMS prevalence was 10.8% (95% CI: 8.1-14.2) and 15.5% (95% CI: 13.8-17.4), respectively. Considering the data of 9 studies, the prevalence of FMS in males (n=5243) and females (n=11503) patients was calculated to be 13.7% (95% CI: 10.1-18.2) and 15.4% (95% CI: 10.3-22.4), respectively. The odds ratio of male/female in FMS cases was not statistically significant (OR= 0.9; 95% CI: 0.6-1.2, P=0.55). Subgroup analysis demonstrated a significant difference in the prevalence of FMS between the geographical areas (P= 0.007). The meta-regression model for FMS prevalence was significantly lower in terms of higher latitude (P< 0.001) and increased MS prevalence (P< 0.001). In contrast, meta-regression based on prevalence day was not statistically significant (P=0.29).Conclusions: The prevalence of FMS is more in the pediatric group than that of adults, is distinct between geographical areas, and diminishes with the increment of MS prevalence and latitude. Also, the symptoms initiate relatively at lower ages in FMS cases. By contrast with multifactorial diseases, our analysis unveiled that the prevalence of FMS was not more prevalent in men than women and the risk of MS development in relatives was not more when the affected proband was male.

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