Abstract
Background Vitamin D has been linked to a variety of diseases in observational studies. However, the causal role of vitamin D in human complex traits and diseases being unclear and under much debate. In this study, we used Mendelian randomization (MR) with genetic variants (as instrumental variables) to examine the causal role of vitamin D on various human complex traits and diseases.
Methods We performed MR analysis using genome-wide significant 25(OH)D SNPs from the latest vitamin D GWAS and 45 large-scale meta-GWASs on various outcomes (average sample size=137 112 per GWAS) to determine the causal role of 25(OH)D. We applied MR-Egger regression, MR-PRESSO, and weighted median approach to estimate the causal effect of 25(OH)D while examining and controlling for potential biases from horizontal pleiotropy.
Results We found limited evidence in support for causal effects of 25(OH)D on obesity-related traits, autoimmune diseases, cardiometabolic traits, neurological and psychiatric disorders. Sensitivity analysis using additional vitamin D instruments (association P<10−5) did not show any additional evidence for causal effect of vitamin D. Notably, we identified horizontal pleiotropy for 20% of the trait pairs analyzed here.
Conclusions Despite the largely augmented sample size and substantially improved statistical power with the most recent, largest vitamin D GWAS, our MR analysis did not convincingly support a causal effect of circulating 25(OH)D on complex traits and diseases examined here. Our results can inform ongoing and future randomized clinical trials of vitamin D supplementation. Future studies are warranted to prioritize the most promising target diseases for vitamin D intervention.