PDF(Pubmed)
Abstract：
Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with trans GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a cis DNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm-trait associations generated by EWAS.
摘要：
尽管全表观基因组关联研究（EWAS）已成功鉴定与疾病状态相关的DNA甲基化（DNAm）模式，对疾病的病因机制的任何进一步描述仍然难以捉摸。这种知识差距并非源于缺乏DNAm-性状关联，而是源于影响EWAS结果可解释性的研究设计问题。尽管在预测特定CpG位点的功能方面存在已知的局限性，大多数EWAS坚持广泛的假设，即DNAm的改变会导致最接近基因的转录随之发生变化。这项研究在两个队列中整合了DNAm和基因表达（GE）测量，青少年和年轻成人双胞胎研究（AYATS）和怀孕，种族,环境,基因（PREG）研究，提高对表观基因组调控机制的理解。与顺式GE相关的CpG位点富集在转录因子结合区域和中低CpG密度区域。与反式GE相关的CpG位点也在已知监管意义的区域富集，包括增强子区域。这些结果突出了将DNAm转录本注释限制在小基因组间隔的问题，并质疑假设顺式DNAm-GE途径的有效性。基于这些发现,EWAS结果的解释在没有多组学支持的研究中受到限制,进一步的研究应确定GE相关DNAm过度代表的基因组区域.对GE相关CpG位点的深入表征可以改善对DNAm改变的下游功能影响的预测，并为解释EWAS产生的DNAm性状关联提供最佳实践。
