Adiposity may confound the association between vitamin D and disease risk - a lifecourse Mendelian randomization study.

Background: Vitamin D supplements are widely prescribed to help reduce disease risk. However, this strategy is based on findings using conventional epidemiological methods which are prone to confounding and reverse causation. Methods: In this short report, we leveraged genetic variants which differentially influence body size during childhood and adulthood within a multivariable Mendelian randomization (MR) framework, allowing us to separate the genetically predicted effects of adiposity at these two timepoints in the lifecourse. Results: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), there was strong evidence that higher childhood body size has a direct effect on lower vitamin D levels in early life (mean age: 9.9 years, range = 8.9-11.5 years) after accounting for the effect of the adult body size genetic score (beta = -0.32, 95% CI = -0.54 to -0.10, p=0.004). Conversely, we found evidence that the effect of childhood body size on vitamin D levels in midlife (mean age: 56.5 years, range = 40-69 years) is putatively mediated along the causal pathway involving adulthood adiposity (beta = -0.17, 95% CI = -0.21 to -0.13, p=4.6 × 10 Conclusions: Our findings have important implications in terms of the causal influence of vitamin D deficiency on disease risk. Furthermore, they serve as a compelling proof of concept that the timepoints across the lifecourse at which exposures and outcomes are measured can meaningfully impact overall conclusions drawn by MR studies. Funding: This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).