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

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    Evaluation Summary:

    This manuscript is of broad interest to readers in the fields of vitamin D and obesity. It utilises a Mendelian randomization framework to separate the genetically predicted effects of adiposity at two timepoints in the lifecourse, childhood and adulthood. The key claims of the manuscript are well supported by the data. Higher childhood body size had a direct effect on lower vitamin D levels in early life, while in midlife, childhood body size impacted on adult obesity to result in lower vitamin D levels.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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Abstract

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 -17 ).

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).

Article activity feed

  1. Evaluation Summary:

    This manuscript is of broad interest to readers in the fields of vitamin D and obesity. It utilises a Mendelian randomization framework to separate the genetically predicted effects of adiposity at two timepoints in the lifecourse, childhood and adulthood. The key claims of the manuscript are well supported by the data. Higher childhood body size had a direct effect on lower vitamin D levels in early life, while in midlife, childhood body size impacted on adult obesity to result in lower vitamin D levels.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  2. Reviewer #1 (Public Review):

    Richardson et al. used a multivariable Mendelian randomization framework to separate the genetically predicted effects of adiposity at two timepoints in the lifecourse, childhood and adulthood. They used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Higher childhood body size had a direct effect on lower vitamin D levels in early life, after accounting for the effect of the adult body size genetic score. However in midlife, childhood body size impacted on adult obesity to result in lower vitamin D levels. The authors conclude their findings have important clinical implications in terms of the causal influence of vitamin D deficiency on disease risk. They also serve as a proof of concept that the timepoints across the lifecourse at which exposures and outcomes are measured can impact …

  3. Reviewer #2 (Public Review):

    While several studies have now been performed using time-varying exposures, i.e. PMIDs 35532785, 33749377, 35484151, 35679339, MR studies with time-varying outcomes have been lagging behind. Richardson et al. leveraged time-varying effects of both adiposity and vitamin D levels to investigate the dependency of childhood and adulthood body size on vitamin D levels during childhood and adulthood. Hence, in this way, MR analyses are conducted to the same outcome, measured at different timepoints in the life course.

    Strengths:

    - Usage of both time-varying exposures and outcomes:
    Through exploiting individual-level data on vitamin D status, the authors demonstrate that childhood body size, but not adult body size, has an effect on childhood vitamin D.
    In addition, both childhood and adulthood body size do affect …

  4. Author Response

    Reviewer #2 (Public Review):

    While several studies have now been performed using time-varying exposures, i.e. PMIDs 35532785, 33749377, 35484151, 35679339, MR studies with time-varying outcomes have been lagging behind. Richardson et al. leveraged time-varying effects of both adiposity and vitamin D levels to investigate the dependency of childhood and adulthood body size on vitamin D levels during childhood and adulthood. Hence, in this way, MR analyses are conducted to the same outcome, measured at different timepoints in the life course.

    Strengths:

    Usage of both time-varying exposures and outcomes: Through exploiting individual-level data on vitamin D status, the authors demonstrate that childhood body size, but not adult body size, has an effect on childhood vitamin D.

    In addition, both childhood and …