Teasing out causation in environmental epigenetics

摘要

Background: Epigenetic mechanisms are critical to many cellular processes and diseases. Environmental factors can induce such epigenetic aberrations, which are potential modifiable and reversible preventive and therapeutic targets. Aims: Epigenome-wide association studies are increasingly complimenting GWAS in order to improve understanding of environmental factors with causal health effects. But significant caveats must be considered. Methods and Results: GWAS can infer causality if heritable disease risks flow from DNA to downstream molecular events. Genetic variants are unique in being randomly assigned to germ cells and present in all cells from conception onwards. Despite these Mendelian Randomization principles, genetic associations studies failed to fundamentally improve causal understanding of environmental risks. A key challenge is that human diseases evolve from complex processes, involving epigenomes, transcriptomes, proteomes, metabolomes, and interactomes. Consideration of epigenetics harbours the potential to bring back to light hidden genetic signals masked by a complex interrelationship of genetic variation, downstream molecules, as well as macro- and microenvironment. Epigenetics can provide a causal link between a genetic risk variant and molecular signatures in diseased cells and refine risk estimates for disease entities. Yet, epigenetics faces challenges. Humans possess innumerable epigenomes, differing between cells and changing over time. Current epigenetic studies often rely on blood and other accessible biomaterial in the absence of evidence that this is valid for assessing tissue-specific processes. These and other challenges will be evidenced with specific results from the literature. Conclusions: To apply epigenetics towards causal inference new methods are needed for sophisticated network modeling. Refined disease phenotyping and exposure measurement, longitudinally collected data, and a sophisticated combination of easily accessible and tissue-specific biomaterial are essential to environmental epidemiology.