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

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.

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

Scientific Reports ◽

10.1038/s41598-020-80655-w ◽

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.

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

Journal of Translational Medicine ◽

10.1186/s12967-021-03205-6 ◽

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.

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Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1003605 ◽

2021 ◽

Vol 18 (6) ◽

pp. e1003605

Author(s):

Guillaume Butler-Laporte ◽

Tomoko Nakanishi ◽

Vincent Mooser ◽

David R. Morrison ◽

Tala Abdullah ◽

...

Keyword(s):

Vitamin D ◽

Mendelian Randomization ◽

Causal Effect ◽

Severe Disease ◽

Sensitivity Analyses ◽

European Ancestry ◽

Logarithmic Scale ◽

Host Genetics ◽

A Genome ◽

Vitamin D Levels

Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. Methods and findings Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. Conclusions In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.

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

Frontiers in Genetics ◽

10.3389/fgene.2021.792396 ◽

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 > 0.05). No causal effect of type 2 diabetes on periodontitis was found (all p > 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.

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

Multiple Sclerosis Journal ◽

10.1177/1352458517737373 ◽

2018 ◽

Vol 24 (1) ◽

pp. 80-85 ◽

Cited By ~ 16

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.

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

Neurology Genetics ◽

10.1212/nxg.0000000000000097 ◽

2016 ◽

Vol 2 (5) ◽

pp. e97 ◽

Cited By ~ 94

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

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A mendelian randomization study on causal effects of 25(OH)vitamin D levels on attention deficit/hyperactivity disorder

European Journal of Nutrition ◽

10.1007/s00394-020-02439-2 ◽

2020 ◽

Author(s):

Lars Libuda ◽

Roaa Naaresh ◽

Christine Ludwig ◽

Björn-Hergen Laabs ◽

Jochen Antel ◽

...

Keyword(s):

Vitamin D ◽

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Mendelian Randomization ◽

Causal Effect ◽

European Ancestry ◽

Inverse Association ◽

Hyperactivity Disorder ◽

25 Oh Vitamin D ◽

Mr Study

Abstract Background While observational studies revealed an inverse association between serum 25(OH)vitamin D (25(OH)D) and the risk of attention deficit/hyperactivity disorder (ADHD), the causality of this relationship remains unclear. Methods We conducted a bidirectional two-sample Mendelian Randomization (MR) study to examine whether 25(OH)D has an effect on the risk to develop ADHD or vice versa. Information on single nucleotide polymorphisms (SNP) associated with serum 25(OH)D was obtained from a genome-wide association study (GWAS) considering phenotype data from 79,366 individuals of European ancestry. Data on risk for ADHD were derived from a GWAS analysis with 20,183 individuals diagnosed with ADHD and 35,191 controls. For our analysis, we considered effect sizes based on the European participants (19,099 cases and 34,194 controls). Results Single SNP analyses showed a causal effect of vitamin D on ADHD risk for only one SNP (rs12785878, p = 0.024). The overall MR estimates did not reveal a causal effect of 25(OH)D on risk for ADHD. In the reverse analysis, neither any single nor the multi-SNP MR analyses showed a causal effect of ADHD on 25(OH)D. Conclusion Results from this two-sample MR study did not confirm a causal effect of 25(OH)D on ADHD or vice versa. Accordingly, our study does not provide evidence that improving 25(OH)D via supplementation could reduce the risk of developing ADHD.

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Examining the Causal Inference of Leptin and Soluble Plasma Leptin Receptor Levels on Schizophrenia: A Mendelian Randomization Study

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.753224 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guoqing Chen ◽

Qiuling Wang ◽

Ranran Xue ◽

Xia Liu ◽

Hao Yu

Keyword(s):

Large Scale ◽

Leptin Receptor ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Unit Increase ◽

Plasma Leptin

Background: Observational studies that have supported the role of the leptin level in schizophrenia (SCZ) risk are conflicting. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether the circulating leptin and soluble plasma leptin receptor (sOB-R) levels play a causal role in SCZ risk.Methods: We first selected five independent single-nucleotide polymorphisms (SNPs) associated with the circulating leptin level and three independent SNPs associated with the sOB-R level from two genome-wide association studies (GWASs) of European individuals. Then, we extracted their associations with SCZ using a large-scale GWAS that consisted of 40,675 patients with SCZ and 64,643 controls of European ancestry. We performed an MR analysis using the inverse variance-weighted (IVW) method to examine the causal effect of leptin on SCZ risk. Moreover, we performed sensitivity analyses to verify our MR results using the weighted median and MR-Egger methods.Results: According to the IVW method, genetically predicted circulating leptin levels were not associated with SCZ risk (OR = 1.98, for per 1-SD unit increase in leptin level; 95% CI, 0.87–4.53; p = 0.10). In addition, the sOB-R level showed no causal effect on the SCZ risk using IVW (OR = 0.98 for per 1-SD unit increase in sOB-R level; 95% CI, 0.97–1.00; p = 0.06). Our sensitivity analysis results confirmed our MR findings.Conclusions: By estimating the causal effect of leptin on SCZ risk using the MR methods, we identified no effect of genetically predicted circulating leptin or the sOB-R level on SCZ. As such, our study suggests that leptin might not be a risk factor for SCZ.

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

International Journal of Epidemiology ◽

10.1093/ije/dyaa266 ◽

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.

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