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Publication - Dr Rebecca Richmond

    An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility

    Citation

    Richardson, T, Richmond, R, North, T-L, Hemani, G, Smith, GD, Sharp, G & Relton, C, 2019, ‘An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility’. International Journal of Epidemiology, vol 48., pp. 887?898

    Abstract

    BackgroundThere is mounting evidence that our environment and lifestyle has an impact on epigenetic regulatory mechanisms, such as DNA methylation (DNAm). It has been suggested that these molecular processes may mediate the effect of risk factors on disease susceptibility, although evidence it this regard has been challenging to uncover.Using genetic variants as surrogate variables, we have used two-sample Mendelian randomization (2SMR) to investigate the potential implications of putative changes to DNAm levels on disease susceptibility.
    MethodsTo illustrate our approach, we identified 412 CpG sites where DNAm was associated with smoking and where reverse caution is highly unlikely. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits using findings from large-scale genome-wide association studies. To strengthen evidence of mediatory mechanisms, we used multiple-trait colocalization to assess whether DNA methylation, nearby gene expression and complex trait variation were all influenced by the same causal genetic variant.
    ResultsWe identified 22 associations which survived multiple testing (P<1.89x10-7). In-depth follow-up analyses of particular note suggested that the associations between DNA methylation at the ASPSCR1 and REST/POL2RB gene regions, both linked with reduced lung function, may be mediated by changes in gene expression. We validated associations between DNAm and traits using independent samples from different stages across the life course. 
    ConclusionsOur approach should prove valuable in prioritising CpG sites which may mediate the effect of causal risk factors on disease. In-depth evaluations of findings are necessary to robustly disentangle causality from alternative explanations such as horizontal pleiotropy.

    Full details in the University publications repository