Research ArticleHUMAN GENETICS

DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood

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Science Advances  31 Jan 2018:
Vol. 4, no. 1, eaao4364
DOI: 10.1126/sciadv.aao4364

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  • RE: Response to Richmond et. al: "Why mediation analysis trumps Mendelian randomization in population epigenomics studies of the Dutch Famine"
    • Elmar Tobi, Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center
    • Other Contributors:
      • Erik van Zwet, Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center
      • L.H. Lumey, Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center
      • Bastiaan Heijmans, Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center

    Why mediation analysis trumps Mendelian randomization in population epigenomics studies of the Dutch Famine

    Elmar W. Tobi1,2, Erik W. van Zwet3, L.H. Lumey1,4, Bastiaan T. Heijmans1

    1Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

    2Division of Human Nutrition, Wageningen University and Research, 6708 WE Wageningen, Netherlands.

    3Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

    4Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.

     

    Citable as Tobi EW, Van Zwet EW, Lumey LH, Heijmans BT. BioRxiv 2018; doi: https://doi.org/10.1101/362392

     

    Our recent analysis of genome-wide DNA methylation data in men and women exposed to the Dutch Famine met passionate criticism by several researchers active on Twitter. It also prompted a more reasoned letter by Richmond and colleagues. At the core of the debate is the proper interpretation of findings from a mediation analysis. We used this method to identify specific DNA methylation changes that statistically provide a link between prenatal exposure to famine and adult metabolic traits. Our c...

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    Competing Interests: None declared.
  • Editorial Addendum

    Editorial Update:

    Please note that one of the author's names is listed incorrectly, and should be George Davey Smith.

    The author list is:

    Rebecca Richmond
    Caroline Relton
    George Davey Smith
     

    Best,

    The Science Advances Editorial Team.

    Competing Interests: None declared.
  • RE: What evidence is required to suggest that DNA methylation mediates the association between prenatal famine exposure and adulthood disease?
    • George Cavey Smith, Medical Research Council Integrative Epidemiology Unit, University of Bristol
    • Other Contributors:
      • Rebecca Richmond, Medical Research Council Integrative Epidemiology Unit at the University of Bristol
      • Caroline Relton, Medical Research Council Integrative Epidemiology Unit at the University of Bristol

    What evidence is required to suggest that DNA methylation mediates the association between prenatal famine exposure and adulthood disease?

    Rebecca Richmond, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK

    Caroline Relton, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK

    George Davey Smith, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK

     

    Epigenome-wide associations studies (EWAS) are a key starting point for making inferences about whether DNA methylation lies on a molecular pathway between risk factors and disease. Mediation analysis is an important next step in interpreting observational associations from EWAS but, as highlighted by the recent paper by Tobi et al1, one beset with methodological problems. In the context of a powerful natural experiment, the authors provide evidence that DNA methylation mediates associations between prenatal famine exposure and adulthood cardiometabolic disease indicators. To be a mediator a factor must be causal with respect to the outcome and be influenced by the exposure.  Whilst the natural experiment utilized in the study provides strong evidence that the latter may be the case, the design does not protect the former association against confounding or reverse causation.  For exampl...

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    Competing Interests: None declared.

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