A measure of DNA methylation age, the Horvath’s epigenetic clock, has recently emerged as a promising marker to predict mortality. However, the contribution of genetic and environmental factors to the epigenetic clock at... [ view full abstract ]
A measure of DNA methylation age, the Horvath’s epigenetic clock, has recently emerged as a promising marker to predict mortality. However, the contribution of genetic and environmental factors to the epigenetic clock at different old ages is incompletely understood. Therefore, we estimated the magnitude of genetic and environmental influences to the epigenetic clock in 126 (52 MZs, 74 DZs) Swedish and Danish twin pairs at two time points: at mean age of 69 and 79 years. Using the Cholesky decomposition, we also estimated the magnitude of the sources for shared variation between the two ages. The DNA methylation data were assessed in whole blood using the Illumina 450k BeadChip and the epigenetic clock estimates were assessed using the Horvath algorithm. The analyses were adjusted for age, sex, and cell type heterogeneity. Intraclass correlations for MZ and DZs were 0.259 and 0.125 at 69 years and 0.282 and 0.020 at 79 years. The cross-time correlations were 0.341 and 0.294 for MZs and DZs. An AE model best explained the variation at both ages (E=76.6%, A=23.4% at 69 years; E=78.1%, A=21.9% at 79 years). The cross-time covariation was primarily due to A than E (A=69.7%, E=30.3%).
Individual CpG sites contributing to the Horvath’s clock were also evaluated via bivariate Cholesky models within samples using M-values. Among the Swedish samples 53 pairs were selected for comparative analysis with the 43 pairs among the Danish samples. The average broad heritability across 317 sites in the Swedish samples was 19% and 12% at waves 1 and 2, respectively while for the Danish samples across 353 sites it was 24% and 19%, respectively. Significant cross-wave associations were observed in 78% of the Danish but 29% of the CpG sites in the Swedish samples.
Our results demonstrate that most of the variation in the epigenetic clock in old age is due to environmental factors and to a lesser extent due to genetics. However, the genetic sources of variation are largely the same across the old ages whereas those for the environmental ones seem to differ more.
