Objective To determine if circulating concentrations of
vitamin D are causally associated with risk of
cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of
Colorectal Cancer Consortium (GECCO), and the
Prostate Cancer Association Group to Investigate
Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of
cancer (22 898
prostate cancer, 15 748
breast cancer, 12 537
lung cancer, 11 488
colorectal cancer, 4369
ovarian cancer, 1896
pancreatic cancer, and 1627
neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with
vitamin D were used to define a multi-polymorphism score for circulating
25-hydroxyvitamin D (25(
OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and
pancreatic cancer and
neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on
cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(
OH)D was associated with risk of any of the seven
cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(
OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for
colorectal cancer, 1.05 (0.89 to 1.24) for
breast cancer, 0.89 (0.77 to 1.02) for
prostate cancer, and 1.03 (0.87 to 1.23) for
lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(
OH)D for most primary
cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating
vitamin D concentration and risk of various types of
cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for
vitamin D deficiency and subsequent widespread
vitamin D supplementation should not currently be recommended as a strategy for primary
cancer prevention.