Vitamin D and the Risk of Depression: A Causal Relationship? Findings from a Mendelian Randomization Study

While observational studies show an association between 25(OH)vitamin D concentrations and depressive symptoms, intervention studies, which examine the preventive effects of vitamin D supplementation on the development of depression, are lacking. To estimate the role of lowered 25(OH)vitamin D concentrations in the etiology of depressive disorders, we conducted a two-sample Mendelian randomization (MR) study on depression, i.e., “depressive symptoms” (DS, n = 161,460) and “broad depression” (BD, n = 113,769 cases and 208,811 controls). Six single nucleotide polymorphisms (SNPs), which were genome-wide significantly associated with 25(OH)vitamin D concentrations in 79,366 subjects from the SUNLIGHT genome-wide association study (GWAS), were used as an instrumental variable. None of the six SNPs was associated with DS or BD (all p > 0.05). MR analysis revealed no causal effects of 25(OH)vitamin D concentration, either on DS (inverse variance weighted (IVW); b = 0.025, SE = 0.038, p = 0.52) or on BD (IVW; b = 0.020, SE = 0.012, p = 0.10). Sensitivity analyses confirmed that 25(OH)vitamin D concentrations were not significantly associated with DS or BD. The findings from this MR study indicate no causal relationship between vitamin D concentrations and depressive symptoms, or broad depression. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.

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Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and obesity

10.1101/2021.06.16.448665 ◽

2021 ◽

Author(s):

German Dario Carrasquilla ◽

Mario García-Ureña ◽

Tove Fall ◽

Thorkild IA Sørensen ◽

Tuomas Kilpeláinen

Keyword(s):

Physical Activity ◽

Weight Gain ◽

Causal Relationship ◽

Physical Inactivity ◽

Observational Studies ◽

Sedentary Time ◽

Mendelian Randomization ◽

Genome Wide Association Studies ◽

Reverse Causality ◽

Genome Wide

Physical inactivity is associated with excess weight gain in observational studies. However, some longitudinal studies indicate reverse causality where weight gain leads to physical inactivity. As observational studies suffer from reverse causality, it is challenging to assess the true causal directions. Here, we assess the bidirectional causality between physical inactivity and obesity by bidirectional Mendelian randomization analysis. We used results from genome-wide association studies for accelerometer-based physical activity and sedentary time in 91,105 individuals and for body mass index (BMI) in 806,834 individuals. We implemented Mendelian randomization using CAUSE method that accounts for pleiotropy and sample overlap using full genome-wide data. We also applied inverse variance-weighted, MR-Egger, weighted median, and weighted mode methods using genome-wide significant variants only. We found evidence of bidirectional causality between sedentary time and BMI: longer sedentary time was causally associated with higher BMI [beta (95%CI) from CAUSE method: 0.11 (0.02, 0.2), P=0.02], and higher BMI was causally associated with longer sedentary time (0.13 (0.08, 0.17), P=6.3.x10-4). Our analyses suggest that higher moderate and vigorous physical activity are causally associated with lower BMI (moderate: -0.18 (-0.3,-0.05), P=0.006; vigorous: -0.16 (-0.24,-0.08), P=3.8x10-4), but indicate that the association between higher BMI and lower levels of physical activity is due to horizontal pleiotropy. The bidirectional, causal relationship between sedentary time and BMI suggests that decreasing sedentary time is beneficial for weight management, but also that targeting obesity may lead to additional health benefits by reducing sedentary time.

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Causal Association Between Birth Weight and Atrial Fibrillation: Evidence from a Two-Sample Mendelian Randomization Analysis

10.21203/rs.3.rs-36815/v1 ◽

2020 ◽

Author(s):

Songzan Chen ◽

Fangkun Yan ◽

Tian Xu ◽

Yao Wang ◽

Kaijie Zhang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Birth Weight ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

P Value ◽

Causal Association ◽

Genome Wide ◽

A Genome ◽

Mr Study

Abstract Background Although several observational studies have shown an association between birth weight (BW) and atrial fibrillation (AF), controversy remains. In this study, we aimed to explore the role of elevated BW on the etiology of AF. Methods A two-sample Mendelian randomization (MR) study was designed to infer the causality. The genetic data on the associations of single nucleotide polymorphisms (SNPs) with BW and AF were separately obtained from two large-scale genome-wide association study with up to 321,223 and 1,030,836 individuals respectively. SNPs were identified at a genome-wide significant level (p-value < 5 × 10− 8). The inverse variance-weighted (IVW) with fixed effects method was performed to obtain causal estimates as our primary analysis. MR-Egger regression was conducted to assess the pleiotropy and sensitivity analyses with various statistical methods were applied to evaluate the robustness of the results. Results In total, 122 SNPs were identified as the genetic instrumental variables. MR analysis revealed a causal effect of elevated BW on AF (OR = 1.21, 95% CI = 1.13–1.29, p-value = 2.39 × 10− 8). The MR-Egger regression suggested no evidence of directional pleiotropy (intercept = 0.00, p-value = 0.62). All the results in sensitivity analyses were consistent with the primary result, which confirmed the causal association between BW and AF. Conclusions The findings from the two-sample MR study indicate a causal effect of elevated BW on AF. This suggests a convenient and effective method to ease the burden of AF by reducing the number of newborns with elevated BW.

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Circulating Vitamin D Levels and Risk of Vitiligo: Evidence From Meta-Analysis and Two-Sample Mendelian Randomization

Frontiers in Nutrition ◽

10.3389/fnut.2021.782270 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jie Song ◽

Ke Liu ◽

Weiwei Chen ◽

Bin Liu ◽

Hong Yang ◽

...

Keyword(s):

Vitamin D ◽

Observational Studies ◽

Mendelian Randomization ◽

Meta Analysis ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Hydroxyvitamin D ◽

Vitamin D Levels ◽

Significant Difference ◽

25 Hydroxyvitamin D

Background: The association between circulating vitamin D levels and risk of vitiligo was inconsistent among observational studies, and whether these observed associations were causal remained unclear. Therefore, we aimed to evaluate the effect of vitamin D on the risk of vitiigo using meta-analysis and Mendelian randomization (MR).Methods: At the meta-analysis stage, literature search was performed in PubMed and Web of Science to identify eligible observational studies examining the association of circulating 25-hydroxyvitamin D [25(OH)D] or 25-hydroxyvitamin D3 [25(OH)D3] levels with risk of vitiligo up to April 30, 2021. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) of 25(OH)D and 25(OH)D3 in patients with vitiligo relative to controls were pooled. Then at the MR stage, genetic instruments for circulating 25(OH)D (N = 120,618) and 25(OH)D3 (N = 40,562) levels were selected from a meta-analysis of genome-wide association studies (GWAS) of European descent, and summary statistics of vitiligo were obtained from a meta-analysis of three GWASs including 4,680 cases and 39,586 controls. We used inverse-variance weighted (IVW) as main method, followed by weighted-median and likelihood-based methods. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.Results: In the meta-analysis, patients with vitiligo had a lower level of circulating 25(OH)D compared with controls [SMD = −1.40; 95% confidence interval (CI): −1.91, −0.89; P < 0.001], while no statistically significant difference of 25(OH)D3 between vitiligo cases and controls was found (SMD = −0.63; 95% CI: −1.29, 0.04; P = 0.064). However, in the MR analyses, genetically predicted 25(OH)D [odds ratio (OR) = 0.93, 95% CI = 0.66–1.31, P = 0.66] and 25(OH)D3 levels (OR = 0.95, 95% CI = 0.80–1.14, P = 0.60) had null associations with risk of vitiligo using the IVW method. Sensitivity analyses using alternative MR methods and instrumental variables (IV) sets obtained consistent results, and no evidence of pleiotropy or outliers was observed.Conclusion: Our study provided no convincing evidence for a causal effect of 25(OH)D or 25(OH)D3 levels on the risk of vitiligo. Further longitudinal and experimental studies, as well as functional studies are warranted to elucidate the role of vitamin D in the development of vitiligo.

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Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1003536 ◽

2021 ◽

Vol 18 (2) ◽

pp. e1003536

Author(s):

Despoina Manousaki ◽

Adil Harroud ◽

Ruth E. Mitchell ◽

Stephanie Ross ◽

Vince Forgetta ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Mendelian Randomization ◽

Diabetes Risk ◽

Sensitivity Analyses ◽

Substantial Impact ◽

Genome Wide ◽

Inverse Variance ◽

Vitamin D Levels

Background Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). Methods and findings For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D–insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. Conclusions Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.

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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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Association of Autism Spectrum Disorder, Neuroticism, and Subjective Well-Being With Cardiovascular Diseases: A Two-Sample Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.676030 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xingang Sun ◽

Lu Chen ◽

Zhen Wang ◽

Yunlong Lu ◽

Miao Chen ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Cardiovascular Diseases ◽

Mendelian Randomization ◽

Well Being ◽

Autism Spectrum ◽

Sensitivity Analyses ◽

Subjective Well Being ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

Background: Previous observational studies have reported an association between psychiatric traits and cardiovascular diseases (CVDs). In this two-sample Mendelian randomization (MR) study, we aimed to investigate the causality between psychiatric traits and CVDs.Methods: Single-nucleotide polymorphisms (SNPs) associated with autism spectrum disorder (ASD), neuroticism, and subjective well-being at genome-wide significance (P < 1 × 10−8) were identified from genome-wide association studies. Summary-level data of the outcomes, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF), were obtained from several largest datasets. The inverse-variance weighted (IVW) method was used as our main analyses to conduct this MR study. Sensitivity analyses included the weighted median, the MR-robust adjusted profile score (MR-RAPS), and the MR pleiotropy residual sum and outlier (MR-PRESSO) method. Repeated MR analyses using a more relaxed threshold (P < 1 × 10−6) for instruments selection and multivariable MR analyses were also applied to evaluate the robustness of results.Results: The MR analyses showed that genetic predisposition to ASD was associated with a higher risk of AF [odds ratio (OR), 1.109; 95% confidence interval (CI), 1.023–1.201; P = 0.011] and HF (OR, 1.138; 95% CI, 1.036–1.251; P = 0.007). Neuroticism was casually associated with an increased risk of AF (OR, 1.201; 95% CI, 1.037–1.392; P = 0.015), whereas subjective well-being had a protective effect on HF (OR, 0.732; 95% CI, 0.574–0.933; P = 0.012). No other causal association between psychiatric traits and CVDs was observed. Consistent results were obtained in sensitivity analyses.Conclusion: This study provided evidence of causal associations of ASD with a higher risk of AF and HF. Besides, neuroticism was casually associated with an increased risk of AF, and subjective well-being was associated with a decreased risk of HF.

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Genetically Predicted Serum Vitamin D and COVID-19: A Mendelian Randomization Study

Current Developments in Nutrition ◽

10.1093/cdn/nzab053_073 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1080-1080

Author(s):

Bonnie Patchen ◽

Andrew Clark ◽

Nathan Gaddis ◽

Dana Hancock ◽

Patricia Cassano

Keyword(s):

Vitamin D ◽

Observational Studies ◽

Mendelian Randomization ◽

Serum Vitamin ◽

Uk Biobank ◽

Vitamin D Metabolism ◽

Serum Vitamin D ◽

Genome Wide ◽

The Uk ◽

Population Controls

Abstract Objectives Observational studies suggest that low vitamin D levels are associated with increased risk and severity of COVID-19 infection. We used Mendelian randomization (MR) to investigate causality of the vitamin D—COVID-19 association. Methods We constructed a biologically plausible genetic instrument for serum vitamin D based on replicated genome-wide significant variants in genes related to vitamin D metabolism, and evaluated the validity of the genetic instrument in COVID-19 risk subgroups in the UK Biobank. We then performed two sample MR using publically available summary data for the association of the genetic instrument with serum vitamin D in the UK Biobank and with COVID-19 outcomes, including infection, severe respiratory infection, and hospitalization, in the COVID-19 Host Genetics Initiative. We used the inverse-variance weighted MR method for all analyses. Results We found little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. The odds ratio per standard deviation increase in genetically predicted serum vitamin D were: 1.04 (95% confidence interval 0.92 to 1.18) for any COVID-19 infection vs. population controls, 1.05 (0.84–1.31) for hospitalized COVID-19 vs. population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 vs. population controls, 1.15 (0.99 to 1.35) for COVID-19 positive vs. COVID-19 negative and, 1.44 (0.75 to 2.78) for hospitalized COVID-19 vs. non-hospitalized COVID-19. Results were similar in analyses where the genetic instrument included all variants with genome-wide significant associations with serum vitamin D (i.e., including variants with no known relationship to vitamin D metabolism) and where the genetic instrument was for risk of vitamin D deficiency. Conclusions Our results suggest that unconfounded, long-term differences in vitamin D status do not causally affect susceptibility to and severity of COVID-19 infection. These findings are consistent with results of a recently published MR study and suggest that associations seen in observational studies may be driven by confounding. Future directions include extending this work to non-European ancestry populations and high-risk populations, for example persons with comorbid disease. Funding Sources NIDDK, NHLBI and NHGRI of the NIH.

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Systematic Influence of Circulating Bilirubin Levels on Osteoporosis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.719920 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jinqiu Zhao ◽

Muzi Zhang ◽

Zhengxue Quan ◽

Liang Deng ◽

Yongguo Li ◽

...

Keyword(s):

Observational Studies ◽

Genome Wide Association Study ◽

Total Bilirubin ◽

Mendelian Randomization ◽

Meta Analysis ◽

Sensitivity Analyses ◽

P Value ◽

Mineral Density ◽

Causal Risk Factor ◽

Genome Wide

Observational studies report some association between circulating bilirubin levels and osteoporosis, but it is unknown if this association is causal or confounded. In this two-sample Mendelian randomization (MR) study, we included a large genome-wide association study (GWAS) associated with total bilirubin levels among 317,639 people, a large meta-analysis to identify genetic variants associated with bone mineral density (BMD) estimated by heel quantitative ultrasound (eBMD) among 426,824 individuals and fracture among 1.2 million individuals. The results revealed that circulating bilirubin levels had no causal influence on eBMD (beta-estimate: 0.004, 95% confidence interval [CI]: -0.019 to 0.028, SE:0.012, P-value=0.705) or the risk of fracture (beta-estimate: -0.009, 95% CI: -0.035 to 0.017, SE:0.013, P-value=0.488), which were both confirmed by multiple sensitivity analyses. Our results confirm that circulating bilirubin levels have no causal role in eBMD or the incidence of fracture, indicating that circulating bilirubin levels is unlikely to be a causal risk factor for osteoporosis or fracture.

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Systematic review and meta-analysis of the prevalence of depressive symptoms, dysthymia and major depressive disorders among homeless people

BMJ Open ◽

10.1136/bmjopen-2020-040061 ◽

2021 ◽

Vol 11 (2) ◽

pp. e040061

Author(s):

Getinet Ayano ◽

Asmare Belete ◽

Bereket Duko ◽

Light Tsegay ◽

Berihun Assefa Dachew

Keyword(s):

Systematic Review ◽

Depressive Symptoms ◽

Depressive Disorders ◽

Meta Analysis ◽

Random Effect ◽

Homeless People ◽

Sensitivity Analyses ◽

Prevalence Rates ◽

Major Depressive ◽

Major Depressive Disorders

ObjectivesTo assess the global prevalence estimates of depressive symptoms, dysthymia and major depressive disorders (MDDs) among homeless people.DesignSystematic review and meta-analysis.Data sourcesDatabases including PubMed, Scopus and Web of Science were systematically searched up to February 2020 to identify relevant studies that have reported data on the prevalence of depressive symptoms, dysthymia and MDDs among homeless people.Eligibility criteriaOriginal epidemiological studies written in English that addressed the prevalence of depressive problems among homeless people.Data extraction and synthesisA random-effect meta-analysis was performed to pool the prevalence estimated from individual studies. Subgroup and sensitivity analyses were employed to compare the prevalence across the groups as well as to identify the source of heterogeneities. The Joanna Briggs Institute’s quality assessment checklist was used to measure the study quality. Cochran’s Q and the I2 test were used to assess heterogeneity between the studies.ResultsForty publications, including 17 215 participants, were included in the final analysis. This meta-analysis demonstrated considerably higher prevalence rates of depressive symptoms 46.72% (95% CI 37.77% to 55.90%), dysthymia 8.25% (95% CI 4.79% to 11.86%), as well as MDDs 26.24% (95% CI 21.02% to 32.22%) among homeless people. Our subgroup analysis showed that the prevalence of depressive symptoms was high among younger homeless people (<25 years of age), whereas the prevalence of MDD was high among older homeless people (>50 years of age) when compared with adults (25–50 years).ConclusionThis review showed that nearly half, one-fourth and one-tenth of homeless people are suffering from depressive symptoms, dysthymia and MDDs, respectively, which are notably higher than the reported prevalence rates in the general population. The findings suggest the need for appropriate mental health prevention and treatment strategies for this population group.

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Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02494-4 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Maria Bruzelius ◽

Susanna C. Larsson

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

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