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  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.)

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  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 any overall conclusions drawn by MR studies. In particular, the study underlines the significance of obesity in increasing the risk of vitamin D deficiency.

    The strengths of this paper are the robustness and rigour of the methods using an established longitudinal cohort and the Mendelian randomization method.

    A weakness is the lack of contrast of the authors findings from Mendelian randomization with those relevant findings from recent large randomised controlled clinical trials of vitamin D supplementation. In particular, two have shown an interaction between outcomes and BMI, a clinical measure of obesity.

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  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 vitamin D levels during adulthood, however the effect of childhood body size on vitamin D seems to be indirect, as its effect is attenuated when taking adulthood body size into account.
    Hence, these effects are time-specific and illustrate the feasibility of using time-dependent genetic effects in MR to separate effects from early and later life on an outcome measured at different timepoints in the life course.

    Limitations:

    - While multivariable MR is an elegant tool to assess direct and indirect effects of an exposure on outcome, a recent preprint highlights poor performance of multivariable MR to study time-varying causal effects (https://www.medrxiv.org/content/10.1101/2022.03.16.22272492v1). A description of strengths and limitations of MR, and especially of the multivariable MR design is lacking in the Discussion section.

    - Abstract: background and conclusions focus on the influence of vitamin D deficiency on disease risk, hence using vitamin D as an exposure variable. The current study investigates the effects of childhood and adulthood body size on childhood and adulthood vitamin D levels, hence using vitamin D as an outcome variable. I agree that differential time points at which exposures and outcomes are measured may impact conclusions drawn from MR studies, and that childhood/adulthood adiposity may have differential effects on vitamin D levels, during childhood or adulthood. However, as vitamin D is used as an outcome variable in this study, it is less clear how the findings impact the causal influence of vitamin D deficiency on disease risk.

    - Following up on the previous remark, the authors state in the Discussion that adiposity may have acted as a confounding factor on the observed association between vitamin D and T1D (Hypponen et al. 2001). I agree that obesity/adiposity may act as a confounder in observational study designs assessing the effect of vitamin D on disease risk. This is supported by the causal effect of body size on vitamin D levels. However, as also other factors beyond adiposity might influence the observed association between vitamin D and T1D, and hence might explain the discrepancy between observational and MR studies, I would like to suggest rephrasing it more cautionary before jumping to the clinical implications.

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  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 adulthood body size do affect vitamin D levels during adulthood, however the effect of childhood body size on vitamin D seems to be indirect, as its effect is attenuated when taking adulthood body size into account.

    Hence, these effects are time-specific and illustrate the feasibility of using time-dependent genetic effects in MR to separate effects from early and later life on an outcome measured at different timepoints in the life course.

    Limitations:

    While multivariable MR is an elegant tool to assess direct and indirect effects of an exposure on outcome, a recent preprint highlights poor performance of multivariable MR to study time-varying causal effects (https://www.medrxiv.org/content/10.1101/2022.03.16.22272492v1). A description of strengths and limitations of MR, and especially of the multivariable MR design is lacking in the Discussion section.

    Many thanks for this suggestion. The preprint mentioned by the reviewer (which has yet to be peer reviewed at the time of this response) in fact mentions the approach applied in our work where the authors claim that ‘multivariable Mendelian randomization is a legitimate tool for obtaining meaningful inferences in this case.’ That said, we agree that adding some further discussion regarding the strengths and weaknesses of our approach is warranted (page 7):

    ‘Findings from these endeavours should facilitate studies conducting techniques such as lifecourse MR, which can provide insight into the direct and indirect effects of modifiable early life exposures on disease outcomes by harnessing genetic estimates obtained from unprecedented sample sizes when conducted in a two-sample setting. That said, lifecourse MR requires careful examination of genetic instruments to ensure that they are capable of robustly separating the effects of an exposure at different timepoints over the lifecourse (Sanderson et al (2022, in press)).’

    Abstract: background and conclusions focus on the influence of vitamin D deficiency on disease risk, hence using vitamin D as an exposure variable. The current study investigates the effects of childhood and adulthood body size on childhood and adulthood vitamin D levels, hence using vitamin D as an outcome variable. I agree that differential time points at which exposures and outcomes are measured may impact conclusions drawn from MR studies, and that childhood/adulthood adiposity may have differential effects on vitamin D levels, during childhood or adulthood. However, as vitamin D is used as an outcome variable in this study, it is less clear how the findings impact the causal influence of vitamin D deficiency on disease risk.

    We agree with the reviewer that future work is necessary to investigate how the findings of this work may impact disease risk, although this is a substantial undertaking which is outside the scope of this short report. We have therefore added the following to page 6 of our Discussion to make the point that future work is necessary to investigate this:

    ‘Future studies are therefore warranted to disentangle the causal factors which influence disease risk from non-causal confounding factors through the triangulation of multiple lines of evidence including those identified by robustly conducted MR studies.’

    Following up on the previous remark, the authors state in the Discussion that adiposity may have acted as a confounding factor on the observed association between vitamin D and T1D (Hypponen et al. 2001). I agree that obesity/adiposity may act as a confounder in observational study designs assessing the effect of vitamin D on disease risk. This is supported by the causal effect of body size on vitamin D levels. However, as also other factors beyond adiposity might influence the observed association between vitamin D and T1D, and hence might explain the discrepancy between observational and MR studies, I would like to suggest rephrasing it more cautionary before jumping to the clinical implications.

    We have updated this section of the Discussion on page 6 to tone down the clinical implications of our findings by replacing the previous sentence with:

    ‘Evidence from this study therefore highlights the importance of developing a deeper understanding into the role that confounding factors, such as adiposity, may potentially have in distorting observational associations between vitamin D levels and disease risk’

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