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Teasing out causation in environmental epigenetics

机译：消除环境表观遗传学中的因果关系

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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.
机译：背景：表观遗传机制对许多细胞过程和疾病至关重要。环境因素会诱发这种表观遗传畸变，这可能是可修改和可逆的预防和治疗目标。目的：表观基因组范围内的关联研究越来越多地对GWAS进行补充，以增进对因果关系健康影响的环境因素的理解。但是，必须考虑重大警告。方法和结果：如果遗传性疾病风险从DNA转移到下游分子事件，则GWAS可以推断因果关系。遗传变异具有独特性，可以随机分配给生殖细胞，并且从受孕开始就存在于所有细胞中。尽管遵循了孟德尔随机化原则，但遗传关联研究未能从根本上提高对环境风险的因果关系。一个关键的挑战是人类疾病从复杂的过程演变而来，涉及表观基因组，转录组，蛋白质组，代谢组和相互作用组。表观遗传学的考虑蕴藏着使被遗传变异，下游分子以及宏观和微观环境之间复杂的相互关系掩盖的隐藏遗传信号的潜力。表观遗传学可以提供遗传风险变异与患病细胞中分子标记之间的因果关系，并完善疾病实体的风险估计。然而，表观遗传学面临挑战。人类拥有无数的表观基因组，在细胞之间存在差异，并随着时间而变化。当前的表观遗传学研究通常依赖于血液和其他可获取的生物材料，而没有证据表明这对评估组织特异性过程有效。这些和其他挑战将通过文献的具体结果得到证明。结论：要将表观遗传学应用于因果推理，需要新的方法来进行复杂的网络建模。精细的疾病表型和暴露测量，纵向收集的数据以及易于获取的和特定于组织的生物材料的复杂组合对于环境流行病学至关重要。

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