Phenome-wide Mendelian-randomization study of genetically determined vitamin D on multiple health outcomes using the UK Biobank study

Abstract

BackgroundVitamin D deficiency is highly prevalent across the globe. Existing studies suggest that a low vitamin D level is associated with more than 130 outcomes. Exploring the causal role of vitamin D in health outcomes could support or question vitamin D supplementation.MethodsWe carried out a systematic literature review of previous Mendelian-randomization studies on vitamin D. We then implemented a Mendelian Randomization–Phenome Wide Association Study (MR-PheWAS) analysis on data from 339 256 individuals of White British origin from UK Biobank. We first ran a PheWAS analysis to test the associations between a 25(OH)D polygenic risk score and 920 disease outcomes, and then nine phenotypes (i.e. systolic blood pressure, diastolic blood pressure, risk of hypertension, T2D, ischaemic heart disease, body mass index, depression, non-vertebral fracture and all-cause mortality) that met the pre-defined inclusion criteria for further analysis were examined by multiple MR analytical approaches to explore causality.ResultsThe PheWAS analysis did not identify any health outcome associated with the 25(OH)D polygenic risk score. Although a selection of nine outcomes were reported in previous Mendelian-randomization studies or umbrella reviews to be associated with vitamin D, our MR analysis, with substantial study power (>80% power to detect an association with an odds ratio >1.2 for per standard deviation increase of log-transformed 25[OH]D), was unable to support an interpretation of causal association.ConclusionsWe investigated the putative causal effects of vitamin D on multiple health outcomes in a White population. We did not support a causal effect on any of the disease outcomes tested. However, we cannot exclude small causal effects or effects on outcomes that we did not have enough power to explore due to the small number of cases.

Vitamin D Supplementation for Prevention of Type 2 Diabetes Mellitus: To D or Not to D?

“…In a Danish study of 96 423 adults, genetic variants associated with low blood 25(OH)D levels predicted incident type 2 diabetes ( 33 ). However, other studies in different cohorts have reported no associations between genetic variants that specifically affect blood 25(OH)D level and incident diabetes ( 30–32 , 34 ). Mendelian randomization studies center upon certain assumptions that may not apply to vitamin D. Specifically, the tested alleles accounted for less than 5% of the variance in blood 25(OH)D level.…”

Review of Recent Advances in Understanding the Role of Vitamin D in Reducing Cancer Risk: Breast, Colorectal, Prostate, and Overall Cancer

“…As shown for breast cancer, risk changes more rapidly below 20 ng/ml than above 20 ng/ml (16). A recent article on the MR study stated (46) Another MR study published around the same time supported that statement. For the Copenhagen data sets, the HR for a 10-ng/ml increase in the MR genetically determined 25(OH)D concentration and cancer mortality rate was 0.97 (95% CI=0.94-1.10; p=0.06), whereas the HR for 10 ng/ml of serum 25(OH)D concentration was 0.93 (95% CI=0.88-0.98) (47).…”

Role of Vitamin D in Preventing and Treating Selected Extraskeletal Diseases—An Umbrella Review

“…A Mendelian randomisation study analysing depressive symptoms and broadly defined depression in two large population studies (> 480,000 participants) did not find an association of the alleles linked to serum 25(OH)D with these depression phenotypes [189]. The Mendelian randomisation study with 339,256 UK biobank participants (including 23,294 cases with depression) by Meng et al (2019) did also not support a causal role of life-long serum 25(OH)D reduction on depression [190].…”

“…In contrast, Mendelian randomisation studies do not support a causal role of (genetically) lower levels of serum 25(OH)D on the development of depressive symptoms or major depressive disorders. Recently, two additional Mendelian randomisation studies concerning 25(OH)D and depression were published (after the search period) [189,190]. A Mendelian randomisation study analysing depressive symptoms and broadly defined depression in two large population studies (> 480,000 participants) did not find an association of the alleles linked to serum 25(OH)D with these depression phenotypes [189].…”