Epidemiology and Biostatistics, Department of Public Health, Faculty of Health Science, University of Southern Denmark, J. B. Winsløws Vej 9B, DK-5000, Odense, Denmark.
Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Clin Epigenetics. 2019 Feb 8;11(1):23. doi: 10.1186/s13148-019-0622-4.
Multiple epigenome-wide association studies have been performed to identify DNA methylation patterns regulated by aging or correlated with risk of death. However, the inter-relatedness of the epigenetic basis of aging and mortality has not been well investigated.
Using genome-wide DNA methylation data from the Lothian Birth Cohorts, we conducted a genome-wide association analysis of all-cause mortality and compared this with age-associated methylation patterns reported on the same samples.
Survival analysis using the Cox regression model identified 2552 CpG sites with genome-wide significance (false discovery rate < 0.05) for all-cause mortality. CpGs whose methylation levels are associated with increased mortality appear more distributed from the gene body to the intergenic regions whereas CpGs whose methylation levels are associated with decreased mortality is more concentrated at the promoter regions. In comparison with reported CpGs displaying significant age-dependent methylation patterns in the same samples, we observed a limited but highly significant overlap between mortality-associated and age-associated CpGs (p value 2.52e-06). Most importantly, the overlapping CpGs are dominated by those whose overall age-related methylation patterns reduce the risk of death.
All-cause mortality is significantly associated with altered methylation at multiple genomic sites with differential distribution in gene regions for CpGs correlated with increased or decreased risk of death. The age-dependent methylation changes could reflect an active response to the aging process that contributes to maintain individual survival.
已经进行了多项表观基因组全基因组关联研究，以鉴定受衰老调控或与死亡风险相关的 DNA 甲基化模式。然而，衰老和死亡率的表观遗传学基础之间的相互关系尚未得到很好的研究。
我们使用来自洛锡安出生队列的全基因组 DNA 甲基化数据，对全因死亡率进行了全基因组关联分析，并将其与在相同样本中报告的与年龄相关的甲基化模式进行了比较。
使用 Cox 回归模型进行的生存分析确定了与全因死亡率具有全基因组显著性（错误发现率<0.05）的 2552 个 CpG 位点。与死亡率相关的 CpG 其甲基化水平与增加的死亡率相关的 CpG 似乎更多地分布在基因体到基因间区域，而与死亡率相关的 CpG 其甲基化水平与降低的死亡率相关的 CpG 则更集中在启动子区域。与在相同样本中显示出显著的年龄相关甲基化模式的报道 CpG 相比，我们观察到死亡率相关和年龄相关的 CpG 之间存在有限但高度显著的重叠（p 值为 2.52e-06）。最重要的是，重叠的 CpG 主要由那些整体上与年龄相关的甲基化模式降低死亡风险的 CpG 主导。
全因死亡率与多个基因组位点的改变甲基化显著相关，与死亡率增加或降低相关的 CpG 在基因区域的分布存在差异。与年龄相关的甲基化变化可能反映了对衰老过程的积极反应，有助于维持个体的生存。
