Dataset Information

Phenome-wide Mendelian randomization study evaluating the association of circulating vitamin D with complex diseases.

ABSTRACT:

Background

Circulating vitamin D has been associated with multiple clinical diseases in observational studies, but the association was inconsistent due to the presence of confounders. We conducted a bidirectional Mendelian randomization (MR) study to explore the healthy atlas of vitamin D in many clinical traits and evaluate their causal association.

Methods

Based on a large-scale genome-wide association study (GWAS), the single nucleotide polymorphism (SNPs) instruments of circulating 25-hydroxyvitamin D (25OHD) from 443,734 Europeans and the corresponding effects of 10 clinical diseases and 42 clinical traits in the European population were recruited to conduct a bidirectional two-sample Mendelian randomization study. Under the network of Mendelian randomization analysis, inverse-variance weighting (IVW), weighted median, weighted mode, and Mendelian randomization (MR)-Egger regression were performed to explore the causal effects and pleiotropy. Mendelian randomization pleiotropy RESidual Sum and Outlier (MR-PRESSO) was conducted to uncover and exclude pleiotropic SNPs.

Results

The results revealed that genetically decreased vitamin D was inversely related to the estimated BMD (β = -0.029 g/cm², p = 0.027), TC (β = -0.269 mmol/L, p = 0.006), TG (β = -0.208 mmol/L, p = 0.002), and pulse pressure (β = -0.241 mmHg, p = 0.043), while positively associated with lymphocyte count (β = 0.037%, p = 0.015). The results did not reveal any causal association of vitamin D with clinical diseases. On the contrary, genetically protected CKD was significantly associated with increased vitamin D (β = 0.056, p = 2.361 × 10^-26).

Conclusion

The putative causal effects of circulating vitamin D on estimated bone mass, plasma triglyceride, and total cholesterol were uncovered, but not on clinical diseases. Vitamin D may be linked to clinical disease by affecting health-related metabolic markers.

SUBMITTER: Xu JJ

PROVIDER: S-EPMC10095159 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Phenome-wide Mendelian randomization study evaluating the association of circulating vitamin D with complex diseases.

Xu Jin-Jian JJ Zhang Xiao-Bin XB Tong Wen-Tao WT Ying Teng T Liu Ke-Qi KQ

Frontiers in nutrition 20230329

<h4>Background</h4>Circulating vitamin D has been associated with multiple clinical diseases in observational studies, but the association was inconsistent due to the presence of confounders. We conducted a bidirectional Mendelian randomization (MR) study to explore the healthy atlas of vitamin D in many clinical traits and evaluate their causal association.<h4>Methods</h4>Based on a large-scale genome-wide association study (GWAS), the single nucleotide polymorphism (SNPs) instruments of circul ...[more]

PMID: 37063319

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Project description:BackgroundPrevious observational studies have shown conflicting results of vitamins supplementation for thyroid diseases. The causal relationships between vitamins and thyroid diseases are unclear. Therefore, we conducted a two-sample bidirectional Mendelian randomization (MR) study to explore association of circulating vitamin levels with thyroid diseases.MethodsWe performed a bidirectional MR analysis using genome-wide association study (GWAS) data. Genetic tool variables for circulating vitamin levels include vitamins A, B9, B12, C, D, and E, Genetic tool variables of thyroid diseases include autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid nodules (TNs), and Thyroid cancer (TC). Inverse-variance weighted multiplicative random effects (IVW-RE) was mainly used for MR Analysis, weighted median (WM) and MR Egger were used as supplementary methods to evaluate the relationships between circulating vitamin levels and thyroid diseases. Sensitivity and pluripotency were evaluated by Cochran's Q test, MR-PRESSO, Radial MR, MR-Egger regression and leave-one-out analysis.ResultsPositive MR evidence suggested that circulating vitamin C level is a protective factor in autoimmune hypothyroidism (ORIVW-RE=0.69, 95%CI: 0.58-0.83, p = 1.05E-04). Reverse MR Evidence showed that genetic susceptibility to autoimmune hyperthyroidism is associated with reduced level of circulating vitamin A(ORIVW-RE = 0.97, 95% CI: 0.95-1.00, p = 4.38E-02), genetic susceptibility of TNs was associated with an increased level of circulating vitamin D (ORIVW-RE = 1.02, 95% CI: 1.00-1.03, p = 6.86E-03). No causal and reverse causal relationship was detected between other circulating vitamin levels and thyroid diseases.ConclusionOur findings provide genetic evidence supporting a bi-directional causal relationship between circulating vitamin levels and thyroid diseases. These findings provide information for the clinical application of vitamins prevention and treatment of thyroid diseases.

Project description:BackgroundAge at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner.MethodsWe conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations.ResultsOf the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null.ConclusionsThe genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

Dataset Information

Phenome-wide Mendelian randomization study evaluating the association of circulating vitamin D with complex diseases.

Background

Methods

Results

Conclusion

Publications

Phenome-wide Mendelian randomization study evaluating the association of circulating vitamin D with complex diseases.

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