Genetically predicted 25-Hydroxyvitamin D levels on Hypothyroidism: A two-sample Mendelian Randomization

Background Alterations in levels of 25-Hydroxyvitamin D have been associated with the risk of thyroid disease. This study uses Mendelian randomization (MR) to infer the possible causal association of 25-Hydroxyvitamin D with hypothyroidism. Methods We performed two-sample MR using the summary statistics data from genome-wide association studies (GWAS) from populations with European ancestry to infer the causality of genetically controlled levels of 25-Hydroxyvitamin D on the risk of hypothyroidism, Hashimoto’s thyroiditis, as well as biochemical parameters of thyroid diseases. The inverse-variance method (IVW) was used as the primary method to calculate the combined effect of all SNPs. Other methods were adopted to evaluate the stability and reliability of the results. Comprehensive sensitivity analyses were conducted to ensure that none of the MR analysis’s primary assumptions were violated. Results The results of the IVW analysis revealed a significant causal association between higher levels of 25-Hydroxyvitamin D and lower risk of hypothyroidism (beta = −0.197, 95% CI (− 0.301, −0.093); SE = 0.053, Pbeta = 2.256×10-4) as well as increased levels of free T4 (beta = 0.204, 95% CI (0.305, 0.094); SE = 0.056, Pbeta = 3.0506×10−4). On the other hand, no significant causality was determined for higher levels of 25-Hydroxyvitamin D in association with Hashimoto’s thyroiditis (beta=-0.047, 95% CI (−0.245, 0.151), p=0.641) and TSH levels (beta = −0.024, 95% CI (−0.099, - 0.051); Pbeta = 0.524). Conclusion The results of this two-sample MR study provide evidence supporting the potential of 25-Hydroxyvitamin D supplementation in reducing the risk of hypothyroidism. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets analyzed during the current study are publicly available and were extracted from the GWAS catalog database and the ThyroidOmics Consortium. The process of MR analyses and the results are publicly available through the following HTML link: * CI : Confidence interval GWAS : Genome-Wide Association Study IVs : Instrumental Variables IVW : Inverse Variance-Weighted MAF : Mean Allele Frequency MBE : Mode-Based Estimation MR : Mendelian Randomization MR-PRESSO : Mendelian Randomization Pleiotropy RESidual Sum and Outlier RCT : Randomized Clinical Trial SE : Standard Error SNP : Single Nucleotide Polymorphism TSH : Thyroid Stimulating Hormone fT4 : free T4 VDR : 25-Hydroxyvitamin D Receptor