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 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 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 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.

scholarly journals Tumor Necrosis Factor Inhibition and Parkinson Disease

Neurology ◽  
2021 ◽  
Vol 96 (12) ◽  
pp. e1672-e1679
Author(s):  
Xiaoying Kang ◽  
Alexander Ploner ◽  
Nancy L. Pedersen ◽  
Sara Bandres-Ciga ◽  
Alastair J. Noyce ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Ulcerative Colitis ◽  
Tumor Necrosis Factor ◽  
Crohn Disease ◽  
Tumor Necrosis ◽  
Mendelian Randomization ◽  
Age At Onset ◽  
Multiple Sclerosis Risk ◽  
Necrosis Factor

ObjectiveTo evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of Parkinson disease (PD), we performed a 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics.MethodsGenetic variants in the vicinity of TNFRSF1A, the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS n = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (ncases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson's Disease Genomics Consortium and 23andMe, Inc. To validate variants as proxies of long-term anti-TNF treatment, we also assessed whether variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis, and multiple sclerosis risk (n = 38,589-45,975).ResultsTNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating CRP = 0.99; 95% confidence interval [CI] 0.91–1.08) or age at onset (0.13 years later onset; 95% CI −0.66 to 0.92). In contrast, genetically indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR 0.75; 95% CI 0.65–0.86) and ulcerative colitis (OR 0.84; 95% CI 0.74–0.97) and increased multiple sclerosis risk (OR 1.57; 95% CI 1.36–1.81). Findings were consistent across models using different genetic instruments and Mendelian randomization estimators.ConclusionsOur findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset.Classification of EvidenceThis study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD.

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