Associations between vitamin D and disease risk may be attributed to the confounding influence of adiposity during childhood and adulthood: a lifecourse Mendelian randomization study

Abstract 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 to 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 to 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 −17 ). Conclusions Our findings have important clinical 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.