scholarly journals Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Renxi Wang
Keyword(s):  
Multiple Sclerosis ◽  
Large Scale ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Causal Association ◽  
Serum 25Ohd ◽  
Hydroxyvitamin D ◽  
Simple Mode ◽  
Weighted Median ◽  
25 Hydroxyvitamin D

Abstract Background Observational 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. Methods To 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. Results One 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. Conclusions Our analysis suggested a causal association between genetically increased serum 25OHD levels and reduced MS in the European population.

scholarly journals The Impact of Serum 25-hydroxyvitamin D, Calcium, and Parathyroid Hormone Levels on the Risk of Coronary Artery Disease in Patients With Diabetes: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Songzan Chen ◽  
Fangkun Yang ◽  
Tian Xu ◽  
Yao Wang ◽  
Kaijie Zhang ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Parathyroid Hormone ◽  
Coronary Artery ◽  
Mendelian Randomization ◽  
Causal Association ◽  
Serum 25Ohd ◽  
Hydroxyvitamin D ◽  
Patients With Diabetes ◽  
25 Hydroxyvitamin D ◽  
Artery Disease

Abstract BackgroundTo investigate the causal association between serum 25-hydroxyvitamin D (25OHD), calcium (Ca), and parathyroid hormone (PTH) levels and the risk of coronary artery disease (CAD) in patients with diabetes using a Mendelian randomization approach.MethodsGenetic signatures associated with serum 25OHD, Ca, and PTH levels were extracted from recently published genome-wide association study (GWAS), including 79,366, 39,400, 29,155 individuals, respectively. Genetic association estimates for CAD in patients with diabetes were obtained from a GWAS of 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The inverse-variance-weighted method was employed for the primary analysis, and other robust methods were applied for sensitivity analyses.ResultsSix, seven and five single nucleotide polymorphisms were identified as instrumental variables for serum 25OHD, Ca and PTH levels, respectively. There was no significant association between genetically predicted serum 25OHD levels and the risk of CAD in patients with diabetes (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.58 - 1.87, P = 0.888). Similarly, genetically predicted serum Ca (OR = 1.83, 95% CI: 0.62 – 5.35, P = 0.273) and PTH levels (OR = 1.27, 95% CI: 0.67 – 2.44, P = 0.464) were not significantly associated with the risk of CAD in patients with diabetes. These findings were robust in sensitivity analyses.Conclusions/interpretationThis study found no evidence to support the causal association between serum 25OHD, Ca and PTH levels and the risk of CAD in patients with diabetes.

scholarly journals The impact of serum 25-hydroxyvitamin D, calcium, and parathyroid hormone levels on the risk of coronary artery disease in patients with diabetes: a Mendelian randomization study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Songzan Chen ◽  
Fangkun Yang ◽  
Tian Xu ◽  
Yao Wang ◽  
Kaijie Zhang ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Parathyroid Hormone ◽  
Coronary Artery ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Serum 25Ohd ◽  
Hydroxyvitamin D ◽  
Patients With Diabetes ◽  
25 Hydroxyvitamin D ◽  
Artery Disease

Abstract Background To investigate the causal association between serum 25-hydroxyvitamin D (25OHD), calcium (Ca), and parathyroid hormone (PTH) levels and the risk of coronary artery disease (CAD) in patients with diabetes using a Mendelian randomization approach. Methods Genetic signatures associated with serum 25OHD, Ca, and PTH levels were extracted from recently published genome-wide association study (GWAS), including 79,366, 39,400, 29,155 individuals, respectively. Genetic association estimates for CAD in patients with diabetes were obtained from a GWAS of 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The inverse-variance-weighted method was employed for the primary analysis, and other robust methods were applied for sensitivity analyses. Results Six, seven and five single nucleotide polymorphisms were identified as instrumental variables for serum 25OHD, Ca and PTH levels, respectively. There was no significant association between genetically predicted serum 25OHD levels and the risk of CAD in patients with diabetes (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.58 - 1.87, P = 0.888). Similarly, genetically predicted serum Ca (OR = 1.83, 95% CI: 0.62 – 5.35, P = 0.273) and PTH levels (OR = 1.27, 95% CI: 0.67 – 2.44, P = 0.464) were not significantly associated with the risk of CAD in patients with diabetes. These findings were robust in sensitivity analyses. Conclusions/interpretation Serum 25OHD, Ca and PTH levels may not be causally associated with the risk of CAD in patients with diabetes.

scholarly journals No Causal Association between 25-Hydroxyvitamin D and Features of Skin Aging: Evidence from a Bidirectional Mendelian Randomization Study

2017 ◽  
Vol 137 (11) ◽  
pp. 2291-2297 ◽  
Author(s):  
Raymond Noordam ◽  
Merel A. Hamer ◽  
Luba M. Pardo ◽  
Tamara van der Nat ◽  
Jessica C. Kiefte-de Jong ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Skin Aging ◽  
Causal Association ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D

scholarly journals Association of 25 hydroxyvitamin D concentration with risk of COVID-19: a Mendelian randomization study

2020 ◽  
Author(s):  
Di Liu ◽  
Qiuyue Tian ◽  
Jie Zhang ◽  
Haifeng Hou ◽  
Wei Wang ◽  
...  
Keyword(s):  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
25Ohd Concentration ◽  
25 Hydroxyvitamin D

Background In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal. Methods We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed. Conclusion The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

scholarly journals The relative contributions of obesity, vitamin D, leptin, and adiponectin to multiple sclerosis risk: A Mendelian randomization mediation analysis

2021 ◽  
pp. 135245852199548 ◽  
Author(s):  
Adil Harroud ◽  
Despoina Manousaki ◽  
Guillaume Butler-Laporte ◽  
Ruth E Mitchell ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Mediation Analysis ◽  
Mendelian Randomization ◽  
Vitamin D Supplementation ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
Vitamin D Levels ◽  
25 Hydroxyvitamin D ◽  
Underlying Mechanisms

Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

scholarly journals An Updated Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and the Risk of Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuchen Shi ◽  
Ruifei Liu ◽  
Ying Guo ◽  
Qiwei Li ◽  
Haichun Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Serum Calcium ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Causal Association ◽  
Cognitively Normal ◽  
Gwas Dataset ◽  
Weighted Median ◽  
Normal Controls

It has been a long time that the relationship between serum calcium levels and Alzheimer’s disease (AD) remains unclear. Until recently, observational studies have evaluated the association between serum calcium levels and the risk of AD, however, reported inconsistent findings. Meanwhile, a Mendelian randomization (MR) study had been conducted to test the causal association between serum calcium levels and AD risk, however, only selected 6 serum calcium SNPs as the instrumental variables. Hence, these findings should be further verified using additional more genetic variants and large-scale genome-wide association study (GWAS) dataset to increase the statistical power. Here, we conduct an updated MR analysis of the causal association between serum calcium levels and the risk of AD using a two-stage design. In discovery stage, we conducted a MR analysis using 14 SNPs from serum calcium GWAS dataset (N = 61,079), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). All four MR methods including IVW, weighted median, MR-Egger, and MR-PRESSO showed a reduced trend of AD risk with the increased serum calcium levels. In the replication stage, we performed a MR analysis using 166 SNPs from serum calcium GWAS dataset (N = 305,349), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). Only the weighted median indicated that genetically increased serum calcium level was associated with the reduced risk of AD. Hence, additional studies are required to investigate these findings.

scholarly journals A causal association between schizophrenia and bipolar disorder on rheumatoid arthritis: A two-sample Mendelian randomization study

2021 ◽  
Author(s):  
Gonul Hazal Koc ◽  
Fatih Ozel ◽  
Kaan Okay ◽  
Dogukan Koc
Keyword(s):  
Rheumatoid Arthritis ◽  
Bipolar Disorder ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Causal Association ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median

Background: Schizophrenia(SCZ) and bipolar disorder(BD) are both associated with several autoimmune/inflammatory disorders including rheumatoid arthritis(RA). However, a causal association of SCZ and BD on RA is controversial and elusive. In the present study, we aimed to investigate the causal association of SCZ and BD with RA by using the Mendelian randomization (MR) approach. Methods: A two-sample MR(2SMR) study including the inverse-variance weighted(IVW), weighted median, simple mode, weighted mode and MR-Egger methods were performed. We employed summary-level genome-wide association study(GWAS) data including BD and SCZ as exposure and RA as an outcome. We utilized data from the Psychiatric Genomics Consortium(PGC) for BD(n= 41,917) and SCZ(n= 33,426), whereas RA GWAS dataset (58,284 individuals) from the European ancestry. Results: We obtained independent (r2 <0.001) 48 and 52 single nucleotide polymorphisms (SNPs) from BD and SCZ data at genome-wide significance (p <5x10-8), respectively. Next, these SNPs were utilized as instrumental variables(IVs) in 2SMR analysis to explore the causality of BD and SCZ on RA. The two out of five MR methods showed a statistically significant inverse causal association between BD and RA: weighted median method(odds ratio (OR), 0.869, [95% CI, 0.764-0.989]; P= 0.034) and inverse-variance weighted(IVW) method (OR, 0.810, [95% CI, 0.689-0.953]; P= 0.011). However, we did not find any significant association of SCZ with RA (OR, 1.008, [95% CI, 0.931-1.092]; P= 0.829, using the IVW method). Conclusions: These results provide support for an inverse causal association between BD and RA. Further investigation is needed to explain the underlying protective mechanisms in the development of RA.

scholarly journals Causal Association Between Periodontitis and Type 2 Diabetes: A Bidirectional Two-Sample Mendelian Randomization Analysis

2022 ◽  
Vol 12 ◽  
Author(s):  
Yong-Bo Wang ◽  
Si-Yu Yan ◽  
Xu-Hui Li ◽  
Qiao Huang ◽  
Li-Sha Luo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Bidirectional Association

Background: Previous observational studies have reported a bidirectional association between periodontitis and type 2 diabetes, but the causality of these relationships remains unestablished. We clarified the bidirectional causal association through two-sample Mendelian randomization (MR).Methods: We obtained summary-level data for periodontitis and type 2 diabetes from several published large-scale genome-wide association studies (GWAS) of individuals of European ancestry. For the casual effect of periodontitis on type 2 diabetes, we used five independent single-nucleotide polymorphisms (SNPs) specific to periodontitis from three GWAS. The summary statistics for the associations of exposure-related SNPs with type 2 diabetes were drawn from the GWAS in the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium and the FinnGen consortium R5 release, respectively. For the reversed causal inference, 132 and 49 SNPs associated with type 2 diabetes from the DIAGRAM consortium and the FinnGen consortium R5 release were included, and the summary-level statistics were obtained from the Gene-Lifestyle Interactions in Dental Endpoints consortium. Multiple approaches of MR were carried out.Results: Periodontitis was not causally related with the risk of type 2 diabetes (all p &gt; 0.05). No causal effect of type 2 diabetes on periodontitis was found (all p &gt; 0.05). Estimates were consistent across multiple MR analyses.Conclusion: This study based on genetic data does not support a bidirectional causal association between periodontitis and type 2 diabetes.

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 Association of 25 Hydroxyvitamin D Concentration with Risk of COVID-19: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Di Liu ◽  
Qiuyue Tian ◽  
Jie Zhang ◽  
Haifeng Hou ◽  
Wei Wang ◽  
...  
Keyword(s):  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
25Ohd Concentration ◽  
25 Hydroxyvitamin D

Abstract Background: Coronavirus disease 2019 (COVID-19) has caused a large global pandemic. In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal.Methods: We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results: MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed.Conclusions: The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

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