Svane Anne Marie, Soerensen Mette, Lund Jesper, Tan Qihua, Jylhävä Juulia, Wang Yunzhang, Pedersen Nancy L, Hägg Sara, Debrabant Birgit, Deary Ian J, Christensen Kaare, Christiansen Lene, Hjelmborg Jacob B
Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, 5000 Odense, Denmark.
Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark.
Genes (Basel). 2018 Feb 8;9(2):78. doi: 10.3390/genes9020078.
Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55-90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate ( FDR ) < 0.05 ), of which 24 had an association -value below 10 - 7 . This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples.
多项研究已将单个CpG位点的DNA甲基化与衰老及多种疾病联系起来。近期研究还鉴定出了一些单个CpG，其甲基化水平与全因死亡率相关。在本研究中，我们对来自三项丹麦双胞胎研究的435对同卵双胞胎人群进行了一项全表观基因组研究，以探讨CpG甲基化与死亡率之间的关联。参与者在采血时年龄为55 - 90岁，并随访了长达20年。我们通过与英国和瑞典队列的结果以及文献结果进行比较来验证我们的结果。我们鉴定出了2806个与死亡率相关的CpG位点（错误发现率（FDR）< 0.05），其中24个位点的关联值低于10 - 7。通过控制混杂效应的配对内比较证实了这一点。24个顶级位点中的8个可以在独立数据集中得到验证或被先前的研究证实。对于所有这8个位点，低甲基化与不良生存预后相关，并且7个位点显示出同卵双胞胎相关性高于35%，表明存在潜在的中度至强遗传性，但仍有大量共享或独特环境效应的空间。我们还使用最小绝对收缩和选择算子（LASSO）回归建立了一个死亡率预测模型。该预测模型在丹麦数据的交叉验证下表现良好，但在独立样本中表现不佳。
