Tan Qihua, Heijmans Bastiaan T, Hjelmborg Jacob V B, Soerensen Mette, Christensen Kaare, Christiansen Lene
Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense C, Denmark,
Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense C, Denmark and.
Int J Epidemiol. 2016 Aug;45(4):1146-1158. doi: 10.1093/ije/dyw132. Epub 2016 Aug 6.
Current epigenetic studies on aging are dominated by the cross-sectional design that correlates subjects' ages or age groups with their measured epigenetic profiles. Such studies have been more aimed at age prediction or building up the epigenetic clock of age rather than focusing on the dynamic patterns in epigenetic changes during the aging process.
We performed an epigenome-wide association study of intra-individual longitudinal changes in DNA methylation at CpG (cytosine-phosphate-guanine) sites measured in whole-blood samples of a cohort of 43 elderly twin pairs followed for 10 years (age at intake 73-82 years). Biological pathway analysis and survival analysis were also conducted on CpGs showing longitudinal change in their DNA-methylation levels. Classical twin models were fitted to each CpG site to estimate the genetic and environmental effects on DNA-methylation.
Our analysis identified 2284 CpG sites whose DNA-methylation levels changed longitudinally over the follow-up. Twin modelling revealed that the longitudinal change for 90% of these CpG sites was explained solely by individual unique environmental factors and only for 10% of these sites was it influenced by familial factors (genetic or shared environment). Over 60% of the identified CpG sites were replicated (same direction and replication P < 0.05) in an independent cross-sectional sample of 300 twins aged from 30 to 74 years. The replication rate went up to 91% for the top 53 CpGs with P < 1 × 10-07. Pathway analysis of genes linked to these CpGs identified biologically meaningful gene-sets involved in cellular-signalling events and in transmission across chemical synapses, which are important molecular underpinnings of aging-related degenerative disorders.
Our epigenome-wide association studies on a cohort of old twins followed up for 10 years identified highly replicable epigenetic biomarkers predominantly implicated in signalling pathways of degenerative disorders and survival in the elderly.
当前关于衰老的表观遗传学研究主要采用横断面设计，将受试者的年龄或年龄组与其测得的表观遗传特征相关联。此类研究更多地旨在进行年龄预测或构建年龄表观遗传时钟，而非关注衰老过程中表观遗传变化的动态模式。
我们对43对老年双胞胎队列的全血样本中CpG（胞嘧啶-磷酸-鸟嘌呤）位点的DNA甲基化个体内纵向变化进行了全表观基因组关联研究，该队列随访了10年（入组时年龄为73 - 82岁）。还对DNA甲基化水平呈现纵向变化的CpG进行了生物通路分析和生存分析。对每个CpG位点拟合经典双胞胎模型，以估计遗传和环境对DNA甲基化的影响。
我们的分析确定了2284个CpG位点，其DNA甲基化水平在随访期间发生了纵向变化。双胞胎模型显示，这些CpG位点中90%的纵向变化仅由个体独特的环境因素解释，只有10%的位点受家族因素（遗传或共享环境）影响。在一个由300名年龄在30至74岁的双胞胎组成的独立横断面样本中，超过60%的已鉴定CpG位点被复制（方向相同且复制P < 0.05）。对于P < 1×10 - 07的前53个CpG，复制率高达91%。对与这些CpG相关的基因进行通路分析，确定了参与细胞信号事件和化学突触传递的具有生物学意义的基因集，这些是衰老相关退行性疾病的重要分子基础。
我们对一组老年双胞胎进行了10年随访的全表观基因组关联研究，确定了高度可复制的表观遗传生物标志物，这些标志物主要与退行性疾病的信号通路和老年人的生存有关。
