Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study

Ann Intern Med. 2022 Nov;175(11):1552-1559. doi: 10.7326/M21-3324. Epub 2022 Oct 25.


Background: Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking.

Objective: To assess genetic evidence for the causal role of low vitamin D status in mortality.

Design: Nonlinear Mendelian randomization analyses.

Setting: UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010.

Participants: 307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data.

Measurements: Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020.

Results: There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L.

Limitations: Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate.

Conclusion: Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels.

Primary funding source: National Health and Medical Research Council.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Specimen Banks
  • Cardiovascular Diseases* / epidemiology
  • Humans
  • Mendelian Randomization Analysis
  • Neoplasms* / genetics
  • Prospective Studies
  • Risk Factors
  • United Kingdom / epidemiology
  • Vitamin D
  • Vitamin D Deficiency* / genetics


  • Vitamin D